Method for producing hydrogels

ABSTRACT

The present invention provides a method of producing a polymer hydrogel comprising the steps of: (1) preparing an aqueous solution of a water soluble polysaccharide derivative and a polycarboxylic acid; (2) optionally agitating the solution, for example, by stirring; (3) isolating a polysaccharide derivative/polycarboxylic acid composite from the solution; and (4) heating the polysaccharide derivative/polycarboxylic acid composite at a temperature of at least about 80° C., thereby cross-linking the polysaccharide with the polycarboxylic acid. The invention also provides polymer hydrogels produced by the methods of the invention.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/494,298, filed on Jun. 7, 2011 and U.S. Provisional Application No.61/542,494, filed on Oct. 3, 2011. The entire teachings of the aboveapplication(s) are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Polymer hydrogels are cross-linked hydrophilic polymers which arecapable of absorbing and retaining large amounts of water. Certain ofthese materials are capable of absorbing over 1 Kg of water per gram ofdry polymer. The cross-links between the macromolecular chains form anetwork which guarantees the structural integrity of the polymer-liquidsystem and prevents the complete solubilisation of the polymer whileallowing the retention of the aqueous phase within the molecular mesh.Polymer hydrogels having a particularly large capacity to retain waterare referred to as superabsorbent polymer hydrogels (SAPs). Highabsorbency under load (AUL) is also a common characteristic of SAPswhich is in general is not displayed by polymer hydrogels having lowercapacity to retain water. In addition to pressure, pH and otherenvironmental conditions can affect the water retainment capacity of apolymer hydrogel, such as a SAP. Applications of highly absorbentpolymer hydrogels include as absorbent cores in the field of absorbentpersonal hygiene products (Masuda, F., Superabsorbent Polymers, Ed.Japan Polymer Society, Kyoritsu Shuppann, (1987)) and as devices for thecontrolled release of water and nutrients into arid soils.

Carboxyalkyl cellulose materials and other carboxyalkyl polysaccharidesare known in the art. Carboxyalkyl cellulose materials can be formed bytreating a cellulosic material with a carboxyalkylating agent, such as achloroalkanoic acid, usually monochloroacetic acid, and an alkali, suchas sodium hydroxide, optionally in the presence of an alcohol. Suchcarboxyalkyl celluloses are generally water-soluble. Various methods ofrendering such water-soluble carboxyalkyl celluloses water-insoluble areknown. However, these methods rely on a stabilization mechanism whichdoes not include the use of any cross-linker; the procedure involvesselecting a proper range of temperature and heat treating time totransform the water soluble cellulose derivative into a non-watersoluble form. The resulting stabilization appears to be mainly due tophysical rather than chemical effects. In fact, at certain pH values,generally from about pH 10 and higher, the cellulose derivatives becomewater soluble again. [Flory, J. P. Principles of Polymer Chemistry;Cornell University: Ithaca, N.Y., 1953].

Other methods for the insolubilization of carboxyalkyl cellulosematerials include the heat treatment of the carboxyalkyl cellulose inthe presence of excess carboxyalkylating reactants and by-products ofthe carboxyalkylation reaction, to provide a water-insolublecarboxyalkyl cellulose having desirable liquid absorption and retentionproperties and characteristics. In these cases, the use of acceleratorsand catalysts to promote the stabilization (i.e., permanentcross-linking), coupled to a non uniform distribution of the degree ofcross-linking, result in an insoluble material having a low swellingcapacity (Anbergen U., W. Opperman, Polymer, 31, 1854 (1990), Nijenhuis,K. te, Advances in Polymer Science, 130, (1997)).

Cellulose-based hydrogels can be obtained via either physical orchemical stabilization of aqueous solutions of cellulosics. Additionalnatural and/or synthetic polymers have been combined with cellulose toobtain composite hydrogels with specific properties [Chen, H.; Fan, M.Novel thermally sensitive pH-dependent chitosan/carboxymethylcellulosehydrogels. J. Bioact. Compat. Polym. 2008, 23 (1), 38-48. Chang, C.;Lue, A.; Zhang, L. Effects of cross-linking methods on structure andproperties of cellulose/PVA hydrogels. Macromol. Chem. Phys., 2008, 209(12), 1266-1273] (A. Sannino, M. Madaghiele, F. Conversano, A.Maffezzoli, P. A. Netti, L. Ambrosio and L. Nicolais' “Cellulosederivative-hyaluronic acid based microporous hydrogel cross-linkedthrough divinyl sulfone (DVS) to modulate equilibrium sorption capacityand network stability”, Biomacromolecules, Vol. 5, no 1 (2004) 92-96).Physical, thermoreversible gels are usually prepared from watersolutions of methylcellulose and/or hydroxypropyl methylcellulose (in aconcentration of 1-10% by weight) [Sarkar, N. Thermal gelationproperties of methyl and hydroxypropyl methylcellulose. J. Appl. Polym.Sci., 1979, 24 (4), 1073-1087]. The gelation mechanism involveshydrophobic associations among the macromolecules possessing the methoxygroup. At low temperatures, polymer chains in solution are hydrated andsimply entangled with one another. As temperature increases,macromolecules gradually lose their water of hydration, untilpolymer-polymer hydrophobic associations take place, thus forming thehydrogel network. The sol-gel transition temperature depends on thedegree of substitution of the cellulose ethers as well as on theaddition of salts. A higher degree of substitution of the cellulosederivatives provides them a more hydrophobic character, thus loweringthe transition temperature at which hydrophobic associations take place.A similar effect is obtained by adding salts to the polymer solution,since salts reduce the hydration level of macromolecules by recallingthe presence of water molecules around themselves. Both the degree ofsubstitution and the salt concentration can be properly adjusted toobtain specific formulations gelling at 37° C. and thus potentiallyuseful for biomedical applications [Tate, M. C.; Shear, D. A.; Hoffman,S. W.; Stein, D. G.; LaPlaca, M. C. Biocompatibility ofmethylcellulose-based constructs designed for intracerebral gelationfollowing experimental traumatic brain injury. Biomaterials, 2001, 22(10), 1113-1123. Materials, 2009, 2, 370 Chen, C.; Tsai, C.; Chen, W.;Mi, F.; Liang, H.; Chen, S.; Sung, H. Novel living cell sheet harvestsystem composed of thermoreversible methylcellulose hydrogels.Biomacromolecules, 2006e7 (3), 736-743. Stabenfeldt, S. E.; Garcia, A.J.; LaPlaca, M. C. Thermoreversible laminin-functionalized hydrogel forneural tissue engineering. J. Biomed. Mater. Res., A 2006, 77 (4),718-725.]. However, physically cross-linked hydrogels are reversible [TeNijenhuis, K. On the nature of cross-links in thermoreversible gels.Polym. Bull., 2007, 58 (1), 27-42], and thus might flow under givenconditions (e.g., mechanical loading) and might degrade in anuncontrollable manner. Due to such drawbacks, physical hydrogels basedon methylcellulose and hydroxypropylmethylcellulose (HPMC) are notrecommended for use in vivo.

As opposed to physical hydrogels which show flow properties, stable andstiff networks of cellulose can be prepared by inducing the formation ofchemical, irreversible cross-links among the cellulose chains. Eitherchemical agents or physical treatments (i.e., high-energy radiation) canbe used to form stable cellulose-based networks. The degree ofcross-linking, defined as the number of cross-linking sites per unitvolume of the polymer network, affects the diffusive, mechanical anddegradation properties of the hydrogel, in addition to the sorptionthermodynamics, and can be controlled to a certain extent during thesynthesis. Specific chemical modifications of the cellulose backbonemight be performed before cross-linking, in order to obtain stablehydrogels with given properties. For instance, silylated HPMC has beendeveloped which cross-links through condensation reactions upon adecrease of the pH in water solutions.

As a further example, tyramine-modified sodium carboxymethylcellulose(NaCMC) has been synthesized to obtain enzymatically gellableformulations for cell delivery [Ogushi, Y.; Sakai, S.; Kawakami, K.Synthesis of enzymatically-gellable carboxymethylcellulose forbiomedical applications. J. Biosci. Bioeng., 2007, 104 (1), 30-33].Photocross-linking of aqueous solutions of cellulose derivatives isachievable following proper functionalization of cellulose. However, theuse of chemical cross-linker and/or functionalizing agents provides aproduct which is not suitable for oral administration, especially insignificant amounts and chronic use.

SUMMARY OF THE INVENTION

The present invention relates to the discovery that cross-linkingwater-soluble cellulose derivatives, such as carboxymethylcellulose,with low levels of a polycarboxylic acid, such as citric acid(3-carboxy-3-hydroxy-1,5-pentanedioic acid); hereinafter also designated“CA”) results in the formation of highly absorbent polymer hydrogelshaving significant water absorption properties, mechanical stability andother advantageous characteristics.

The present invention relates, in addition, to improved processes forproducing polymer hydrogels, including superabsorbent polymer hydrogels,by cross-linking a soluble polysaccharide derivative, such as acarboxyalkyl polysaccharide, a hydroxyalkyl polysaccharide or acombination thereof, with a polycarboxylic acid. The invention furtherrelates to the polymer hydrogels produced using these processes andpolymer hydrogels having advantageous properties.

In one embodiment, the invention provides a method of producing apolymer hydrogel comprising the steps of (1) preparing an aqueoussolution of a water soluble polysaccharide derivative and apolycarboxylic acid; (2) optionally agitating the solution, for example,by stirring; (3) isolating a polysaccharide derivative/polycarboxylicacid composite from the solution and (4) heating the polysaccharidederivative/polycarboxylic acid composite at a temperature of at leastabout 80° C., thereby cross-linking the polysaccharide with thepolycarboxylic acid. In one embodiment, the polysaccharidederivative/polycarboxylic acid composite is granulated prior toconducting step (4). In one embodiment, the polysaccharidederivative/polycarboxylic acid composite is heated in step (4) to atemperature of about 100° C. or higher.

The aqueous solution of polysaccharide derivative and polycarboxylicacid is preferably prepared by adding the polysaccharide derivative andthe polycarboxylic acid to water and agitating, for example by stirring,the resulting mixture for a sufficient amount of time to create ahomogenous solution.

The polysaccharide derivative is preferably present in the solution ofstep (1) in a concentration of at least about 0.25% by weight relativeto water, preferably at least about 0.4% or 0.5%. In one embodiment, theconcentration of the polysaccharide derivative is from about 0.25% toabout 25% or about 0.25% to about 30%, by weight relative to water,preferably from about 0.4% to about 20% and more preferably from about0.4% to about 12%. In certain embodiments, the polysaccharide derivativeis present in the solution at a concentration of at least about 4%, forexample from about 4% to about 30%, about 4% to about 20%, about 4% toabout 10% by weight relative to water. In one embodiment, thepolysaccharide derivative is present in the solution of step (1) at aconcentration of about 6% by weight relative to water. In certainembodiments, the polysaccharide concentration is from about 4% to about8%, from about 4.5% to about 7.5%, from about 5% to about 7%, or fromabout 5.5% to about 6.5% by weight relative to water. In otherembodiments, the polysaccharide concentration is 0.25% to about 6%,about 0.4% to about 6% or about 0.5% to about 6% by weight relative towater. In one embodiment, the concentration of the polysaccharidederivative is from about 0.5% to about 1%, 1.5% or 2% by weight relativeto water. In one embodiment, the solution includes undissolvedpolysaccharide derivative, that is, the amount of polysaccharidederivative exceeds its solubility and a suspension or slurry is formed.

The polycarboxylic acid is preferably present in the solution of step(1) in a concentration of about 0.01% to about 5% or about 0.05 to about5% by weight relative to the polysaccharide derivative. Preferably, thepolycarboxylic acid is present in a concentration of about 0.3% or lessor 0.35% or less by weight relative to the polysaccharide derivative. Inan embodiment, the polycarboxylic acid is present in the solution ofstep (1) in a concentration of about 0.01% to about 0.35%, about 0.05%to about 0.35%, about 0.1% to about 0.35%, 0.01% to about 0.3%, about0.05% to about 0.3%, about 0.1% to about 0.3%, 0.15% to about 0.35%,about 0.15% to about 0.3%, 0.2% to about 0.35%, about 0.25% to about0.35%, about 0.2% to about 0.3%, or about 0.25% to about 0.3%, by weightrelative to the polysaccharide derivative.

In another embodiment, the polycarboxylic acid is preferably present inthe solution of step (1) in a concentration of about 0.05 to about 5%(g/g) relative to the monomeric units of the polysaccharide derivative.Preferably, the polycarboxylic acid is present in a concentration ofabout 0.35% (g/g) or 0.3% or less relative to the monomeric units of thepolysaccharide derivative. In an embodiment, the polycarboxylic acid ispresent in the solution of step (1) in a concentration of about 0.05% toabout 0.3%, about 0.1% to about 0.3%, 0.2% to about 0.3% or about 0.25%to about 0.3% (g/g) relative to the monomeric units of thepolysaccharide derivative.

In one embodiment, the aqueous solution consists essentially of thepolysaccharide derivative, the polycarboxylic acid and water. In apreferred embodiment, the solution consists essentially ofcarboxymethylcellulose, citric acid and water.

In another embodiment, the solution consists essentially ofcarboxymethylcellulose, hydroxyethylcellulose, citric acid and water. Inyet another embodiment, the solution consists essentially ofhydroxyethylcellulose, citric acid and water. The water is preferablypurified water, such as distilled or deionized water. In thisembodiment, the process is conducted in the substantial absence of anyother agent that may affect the pH. In embodiments, the solution issubstantially free of a molecular spacer, as this term is used in WO2009/021701, including saccharides, polyols and sugar alcohols, such assorbitol.

In another embodiment, the solution comprises a molecular spacer,preferably a polyhydroxylated compound, such as a saccharide, a polyolor a sugar alcohol. In one embodiment the molecular spacer is sorbitol.Preferably, the concentration of the molecular spacer is from 0% toabout 20% by weight relative to the weight of the water. In oneembodiment the concentration of the molecular spacer is from about 0.1%to about 20% by weight relative to the weight of the water. In anotherembodiment the concentration of the molecular spacer is from about 4% toabout 20% or about 8% to 20% by weight relative to the weight of thewater. In another embodiment, the concentration of the molecular spaceris less than 0.5% by weight relative to the weight of the water, forexample, less than 0.4%, 0.3%, 0.2% or 0.1%. In certain embodiments atlower concentrations of the polycarboxylic acid, a fraction of thepolysaccharide derivative is not crosslinked at the end of the processand can be washed out of the product hydrogel. In this case, the excesspolysaccharide derivative serves as a molecular spacer. This can occur,for example, when the polysaccharide derivative iscarboxymethylcellulose and the polycarboxylic acid is citric acid, at acitric acid concentration of about 0.5 or less, about 0.35% or less orabout 0.3% or less by weight relative to the carboxymethylcellulose.

The cross-linking reaction is preferably conducted in the substantialabsence of a catalyst. In a preferred embodiment, the cross-linkingreaction is conducted in the substantial absence of sodiumhypophosphite.

BRIEF SUMMARY OF THE DRAWINGS

FIG. 1 illustrates the mechanism of cross-linking of a cellulosicpolymer by citric acid.

FIG. 2 is a graph showing the theoretical media uptake and collapse ofan edible polymer hydrogel as it moves through the gastrointestinaltract.

FIG. 3 is a plot of σ (Pa) versus l₀−l (μ) from a typical compressionexperiment as described in Example 5.

FIG. 4 is a plot of −σ(α−1/α²)⁻¹ versus 1/α from a typical compressionexperiment as described in Example 5.

FIG. 5 is a graph showing the degree of cross-linking of citric acidcross-linked carboxymethylcellulose prepared with two different startingCMC concentrations as a function of citric acid concentration.

FIG. 6 is a graph showing the degree of cross-linking of citric acidcross-linked carboxymethylcellulose prepared with different starting CMCconcentrations at 0.3% citric acid.

FIG. 7 is a graph showing the media uptake ratio in SGF/water 1:8 ofcarboxymethylcellulose prepared with different starting CMCconcentrations at 0.3% citric acid.

FIG. 8 presents the HRMAS NMR spectra of samples C and D of Example 6.

FIG. 9 presents the HRMAS NMR spectra of samples A and B of Example 6.

FIG. 10 presents the HRMAS NMR spectrum of samples C and D of Example 6with T2 filtering.

FIG. 11 presents the HRMAS NMR spectrum of samples A and B of Example 6with T2 filtering.

FIG. 12 is a schematic diagram illustrating apparatus useful forproducing a polymer hydrogel.

FIG. 13 presents graphs showing the predicted dependence of elasticmodulus, swelling, viscosity modulus and desirability as a function ofcitric acid concentration as described in Example 9.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides polymer hydrogels, methods of preparingthe polymer hydrogels, methods of use of the polymer hydrogels andarticles of manufacture comprising the polymer hydrogels. In certainembodiments, the invention relates to the discovery that polysaccharidehydrogels, such as carboxymethylcellulose chemically cross-linked withcitric acid, having advantageous properties can be prepared using alower relative amount of polycarboxylic acid than has been taught in theart.

In one embodiment, the method of producing a polymer hydrogel comprisesthe steps of: (1) preparing an aqueous solution of the water solublepolysaccharide derivative and the polycarboxylic acid; (2) optionallyagitating the solution; (3) isolating a polysaccharidederivative/polycarboxylic acid composite from the solution; and (4)heating the polysaccharide derivative/polycarboxylic acid composite at atemperature of at least about 80° C., or at least about 100° C., therebycross-linking the polysaccharide with the polycarboxylic acid andforming the polymer hydrogel. In one embodiment, the polysaccharidederivative/polycarboxylic acid composite is granulated prior toconducting step (4) and optionally sieved to obtain particles of adesired size range. In one embodiment, the polymer hydrogel product ofstep (4) is granulated, for example, by grinding or milling, andoptionally sieved.

In a preferred embodiment, the method of the invention includes thesteps of (1) preparing an aqueous solution of the water solublepolysaccharide derivative and the polycarboxylic acid; (2) agitating thesolution; (3) heating the solution to remove water and produce apolysaccharide derivative/polycarboxylic acid composite; (3a)granulating the polysaccharide derivative/polycarboxylic acid compositeto produce composite particles; (4) heating the composite particles at atemperature of at least about 80° C., thereby cross-linking thepolysaccharide derivative with the polycarboxylic acid and forming thepolymer hydrogel; (5) washing the polymer hydrogel; (6) drying thepolymer hydrogel and, optionally, (7) granulating the polymer hydrogelto produce hydrogel particles. The hydrogel particles produced in eitheror both of steps (3a) and (7) can be sieved to yield a sample ofparticles within a specified size range.

The term “polysaccharide derivative/polycarboxylic acid composite” or“composite” as used herein, refers to a substantially dry materialcomprising a mixture of the polysaccharide derivative and thepolycarboxylic acid. In embodiments in which this composite is producedby evaporative drying of the aqueous solution of polysaccharidederivative and the polycarboxylic acid, the composite is thesubstantially dry residue which remains following removal of the unboundwater. The composition can retain bound water, and can be, for example,up to 5, 10 or 20% water by weight.

Without being bound by theory, it is believed that the preparation ofpolymer hydrogels as disclosed herein proceeds via covalentcross-linking of the polysaccharide derivative with the polycarboxylicacid. FIG. 1 illustrates the cross-linking of a soluble cellulosederivative, such as carboxymethylcellulose, with citric acid. In thismechanism, the C1-carboxyl group of citric acid is activated byanhydride formation at neutral pH and at elevated temperature and in thepresence of a very small amount of water, and in the absence of catalystreacts with a cellulosic hydroxyl group to form an ester. The C5carboxyl group is then activated by anhydride formation and reacts witha hydroxyl group of another cellulosic polymer chain, thereby forming acovalent chemical cross-link. Removal of water from the polysaccharidederivative/polycarboxylic acid solution before crosslinking is thusnecessary to allow the anhydride formation/esterification reaction tooccur. This is performed in steps (3) and (4) described above. As shownin Example 6 below, failure to remove the water from the solution priorto crosslinking results in hydrogels with physical cross-links insteadof chemical cross-links.

The water-soluble polysaccharide derivative is preferably a carboxyalkylpolysaccharide, a hydroxyalkylpolysaccharide or a combination thereof.In certain embodiments, the water-soluble polysaccharide derivative is acellulose derivative, such as a hydroxyalkylcellulose, for example,hydroxyethylcellulose, or a carboxyalkyl cellulose, includingcarboxymethylcellulose, carboxyethyl cellulose, and the like, or amixture thereof. Preferably the polysaccharide derivative iscarboxymethylcellulose or a salt thereof, such as the sodium salt. Incertain embodiments, the polysaccharide derivative consists essentiallyof carboxymethylcellulose. In other embodiments, the polysaccharidederivative is a combination of carboxymethylcellulose with anotherpolysaccharide derivative, such as another cellulose derivative,including a hydroxyalkylcellulose.

Methods of making carboxyalkyl cellulose are known to those skilled inthe art. Suitably, a cellulosic material such as wood pulp fluff,cotton, cotton linters, and the like is provided. The cellulosicmaterial may be in the form of fibers or fibers which have beencomminuted to particulate form. The cellulosic material is dispersed inan inert solvent such as an alcohol and a carboxyalkylating agent isadded to the dispersion. Carboxyalkylating agents generally comprise achloroalkanoic acid such as monochloroacetic acid and sodium hydroxide.It is possible to perform the carboxyalkylation of the startingpolysaccharide in such a manner that the solution of carboxyalkylcellulose and water is formed directly. That is, the carboxyalkylationprocess may be performed in an aqueous medium such that, upon formationof the carboxyalkyl cellulose, it is solubilized in the water. In thismanner, no recovery step is necessary between formation of thecarboxyalkyl cellulose and the formation of the solution of carboxyalkylcellulose and water.

The carboxymethylcellulose or salts thereof preferably have an averagedegree of substitution from about 0.3 to about 1.5, more preferably fromabout 0.4 to about 1.2. The degree of substitution refers to the averagenumber of carboxyl groups present on the anhydroglucose unit of thecellulosic material. Carboxymethylcelluloses having an average degree ofsubstitution within the range of from about 0.3 to about 1.5 aregenerally water-soluble. As used herein, a carboxyalkyl cellulose, suchas carboxymethylcellulose, is considered to be “water-soluble” when itdissolves in water to form a true solution.

Carboxymethylcellulose is commercially available in a wide range ofmolecular weights. Carboxymethylcellulose having a relatively highmolecular weight is preferred for use in the present invention. It isgenerally most convenient to express the molecular weight of acarboxymethylcellulose in terms of its viscosity in a 1.0 weight percentaqueous solution. Carboxymethylcelluloses suitable for use in thepresent invention preferably have a viscosity in a 1.0 weight percentaqueous solution from about 50 centipoise to about 10,000 centipoise,more preferably from about 500 centipoise to about 10,000 centipoise,and most preferably from about 1,000 centipoise to about 2,800centipoise. In one preferred embodiment, the carboxymethylcellulose hasa weighted average molecular weight of 500 to 800 Kd.

Suitable carboxyalkyl celluloses are commercially available fromnumerous vendors. An example of a commercially available carboxyalkylcellulose is carboxymethylcellulose, commercially available fromAshland/Aqualon Company under the trade designation AQUALON™, Blanoseand BONDWELL™ depending on the geographical region in which it is sold.The polycarboxylic acid is preferably an organic acid containing two ormore carboxyl (COOH) groups and from 2 to 9 carbon atoms in the chain orring to which the carboxyl groups are attached; the carboxyl groups arenot included when determining the number of carbon atoms in the chain orring (e.g., 1,2,3 propane tricarboxylic acid would be considered to be aC3 polycarboxylic acid containing three carboxyl groups and 1,2,3,4butanetetracarboxylic acid would be considered to be a C4 polycarboxylicacid containing four carboxyl groups). Alternatively, a heteroatom suchas an oxygen atom or a sulfur atom, can substitute for a methylene groupin the polycarboxylic acid. More specifically, the polycarboxylic acidspreferred for use as cross-linking agents in the present inventioninclude aliphatic and alicyclic acids which are either saturated orolefinically unsaturated, with at least three carboxyl groups permolecule or with two carboxyl groups per molecule and a carbon-carbondouble bond present alpha, beta to one or both carboxyl groups. It isfurther preferred that the polycarboxylic acid have a carboxyl group inan aliphatic or alicyclic polycarboxylic acid which is separated from asecond carboxyl group by 2 or 3 carbon atoms. Without being bound bytheory, it is believed that a carboxyl group of the polycarboxylic acidcan preferably form a cyclic 5- or 6-membered anhydride ring with aneighboring carboxyl group in the polycarboxylic acid molecule. Wheretwo carboxyl groups are separated by a carbon-carbon double bond or areboth connected to the same ring, the two carboxyl groups must be in thecis configuration relative to each other to interact in this manner.

Suitable polycarboxylic acids include citric acid (also known as2-hydroxy-1,2,3 propane tricarboxylic acid), tartrate monosuccinic acid,oxydisuccinic acid also known as 2,2′-oxybis(butanedioic acid),thiodisuccinic acid, disuccinic acid, maleic acid, citraconic acid alsoknown as methylmaleic acid, citric acid, itaconic acid also known asmethylenesuccinic acid, tricarboxylic acid also known as 1,2,3 propanetricarboxylic acid, transaconitic acid also known astrans-1-propene-1,2,3-tricarboxylic acid, 1,2,3,4-butanetetracarboxylicacid, all-cis-1,2,3,4-cyclopentanetetracarboxylic acid, mellitic acidalso known as benzenehexacarboxylic acid, and oxydisuccinic acid alsoknown as 2,2′-oxybis(butanedioic acid). A more detailed description oftartrate monosuccinic acid, tartrate disuccinic acid, and salts thereof,can be found in Bushe et al., U.S. Pat. No. 4,663,071, incorporatedherein by reference.

Preferably, the polycarboxylic acid is saturated and contains at leastthree carboxyl groups per molecule. A preferred polycarboylic acid iscitric acid. Other preferred acids include 1,2,3 propane tricarboxylicacid, and 1,2,3,4 butane tetracarboxylic acid. Citric acid isparticularly preferred, since it provides hydrogels with high levels ofwettability, absorbency and resiliency which are safe and non-irritatingto human tissue, and provides stable, cross-link bonds. Furthermore,citric acid is available in large quantities at relatively low prices,thereby making it commercially feasible for use as the cross-linkingagent.

The above list of specific polycarboxylic acids is for exemplarypurposes only, and is not intended to be all inclusive. Importantly, thecross-linking agent must be capable of reacting with at least twohydroxyl groups on proximately located cellulose chains of two adjacentcellulose molecules. One of skill in the art will recognize that thealiphatic and alicyclic C₂-C₉ polycarboxylic acid cross-linking agentsdescribed above may be reacted in a variety of forms to produce thecross-linked polymer hydrogels herein, such as the free acid form andsalts thereof.

Although the free acid form is preferred, all such forms are meant to beincluded within the scope of the invention.

In one embodiment, the polysaccharide derivative and the polycarboxylicacid are both food grade or pharmaceutical grade materials. For example,carboxymethylcellulose and citric acid are both used as food additivesand pharmaceutical excipients and are, therefore, available in formswhich are suitable for these uses.

The term “carboxymethylcellulose” (CMC), as used herein, refers tocarboxymethylcellulose (cellulose carboxymethyl ether) in the acid form,as a salt or as a combination of the acid form and a salt. Preferredsalt forms include sodium carboxymethylcellulose and potassiumcarboxymethylcellulose. In particularly preferred embodiments, thecarboxymethylcellulose is present in the solution as the sodium salt(NaCMC).

The aqueous solution of the cellulose derivative and the polycarboxylicacid can be formed at any temperature at which the cellulose derivativeis soluble in the water. Generally, such temperatures will be within therange of from about 10° C. to about 100° C. Preferably, the solution isprepared substantially at room temperature, for example, between 20° C.and 30° C.

It is preferred to have the solution pH between 5 and 8, more preferablybetween 6 and 7.

The polysaccharide derivative/polycarboxylic acid composite isolatedfrom the aqueous solution is suitable for chemical cross-linking to formpolymer hydrogels having improved absorption properties due to theinter-chain entanglements. Without being bound by theory, it is believedthat solubilization provides for molecular entanglements which produce atighter network and a preferred distribution of the carboxyl groups andhydroxyl groups between the polysaccharide derivative and thepolycarboxylic acid. Greater entanglement of the polysaccharidederivative chains thus results in a more uniform cross-linking uponheat-treatment, resulting, in turn in a super-absorbent polymer hydrogelwith a greater media uptake capacity and significantly improvedmechanical and rheological properties.

The polysaccharide derivative/polycarboxylic acid composite can beisolated from the solution by any method that avoids substantialdeterioration of the absorption characteristics of the resulting polymerhydrogel. Examples of such methods include evaporative drying, freezedrying, precipitation, centrifugation, spray drying, critical pointdrying, and the like.

Preferably the polysaccharide derivative/polycarboxylic acid compositeis isolated by evaporative drying at a temperature within the range fromabout 10° C. to about 100° C., preferably from about 45° C. to about 80°C. In certain embodiments, drying is conducted at an initial temperaturegreater than 80° C., for example, from 80° C. to 100° C., tosubstantially reduce the solution volume, then the temperature isreduced below 80° C. to complete the drying. For example, the solutioncan be dried initially at 85 C, and then the temperature can be reducedto 50 C to complete the drying. Naturally, higher temperatures can beemployed if the solution is placed under pressure. Lower temperaturescan be employed if the solution is placed under a vacuum. In onepreferred embodiment, evaporative drying is conducted at a temperatureof about 70° C.

When the solution is dried by heating, the step of isolating thepolysaccharide derivative/polycarboxylic acid composite and the step ofcrosslinking the composite can be combined in a single step, preferablywith a temperature change. For example, the drying step can be conductedat a first temperature and then the temperature can be raised to asecond, higher, temperature once drying is complete. Alternatively, thesolution can be dried initially at a higher temperature, for examplefrom about 80° C. to about 100° C. and then, before drying is completethe temperature can be reduced below 80° C. to complete drying. Thetemperature can then be raised to greater than 80° C. to initiatecross-linking. In one embodiment, drying is conducted at an initialtemperature of about 85° C., the temperature is reduced to about 50° C.before drying is complete and then, upon completion of drying, thetemperature is raised to about 120° C.

Other methods of isolation of the composite include precipitation inwhich a precipitating agent (non-solvent), such as methanol, ethanol oracetone is added to the aqueous solution to precipitate the compositefrom solution. The composite can then be recovered by filtration. Ifprecipitation is used to recover the composite, the composite isoptionally washed with water to remove the precipitating agent.Depending on the form in which the composite is recovered, it may benecessary or desirable to alter its form prior to the cross-linkingstep. For example, if evaporative drying is employed, the composite maybe recovered in the form of a film or sheet. This film or sheet materialcan then be granulated, fragmented, ground or comminuted into compositeparticles, flakes or granules prior to the cross-linking step. In oneembodiment, the composite particles are substantially spherical.

If evaporative drying by spray drying is employed, the composite may berecovered in the form of particles, flakes or granules prior to thecross-linking step.

In one embodiment, the composite particles are substantially spherical.In another embodiment, the particles are substantially irregular inform.

The composite particles preferably have a maximum cross-sectionaldiameter or greatest dimension within the range from about 5 micrometersto about 2,000 micrometers, preferably within the range from about 100micrometers to about 1,000 micrometers, and preferably the averageparticle cross-sectional diameter should be from about 300 micrometersto about 800 micrometers.

Without being bound by theory, it is believed that the step ofgranulating the composite prior to cross-linking provides a homogeneousdistribution of cross-linking sites as well as enhanced waterevaporation before the crosslinking reaction begins, resulting in amaterial with high conservative modulus (G′) and uniform chemicalstabilization. This is due to the fact that the thermal gradient infinely granulated particles is more homogeneous than in the bulkstructure, resulting in uniform cross-linking kinetics and efficiency.This also eliminates the problem of the formation of stiffer and weakerareas in the final product, related to higher or lower, respectively,cross-linking degrees. This effect may cause the additional problem ofthe formation of a residual stress in the hydrogel bulk corresponding tosurfaces of differing stiffness, which can in turn lead to delaminationof the material during media uptake, in addition to the already citeddecrease in G′.

The isolated polysaccharide derivative/polycarboxylic acid composite isheat-treated at an elevated temperature to cross-link the polysaccharidederivative. Any combination of temperature and time which achieves adesired degree of cross-linking, without undesirable damage to thepolysaccharide derivative, is suitable for use in the present invention.Preferably the composite is maintained at a temperature of 80° C. orgreater, for example, 100° C. or greater. In certain embodiments, thetemperature is within the range from about 100° C. to about 250° C.,preferably from about 120° C. to about 200° C., and more preferably fromabout 120° C. to about 170° C. In a particularly preferred embodiment,the composite is maintained at about 120° C. The higher the temperaturethat is employed, the shorter the period of time necessary to achievethe desired degree of cross-linking Generally, the heat-treating processwill extend over a time period within the range of from about 1 minuteto about 600 minutes, preferably from about 1 minute to about 240minutes, and more preferably from about 5 minutes to about 120 minutes.

The heat-treating process causes the polysaccharide derivative chains tocross-link via the polycarboxylic acid and become water-insoluble. Theheat-treating process desirably produces a polymer hydrogel having theability to absorb aqueous liquids, in particular stomach fluids whichhave high salinity and low pH.

Any combination of time and temperature which produces a polymerhydrogel having a desired absorbance of an aqueous medium of interestcan be used in the present invention. The ability of a polymer hydrogelto absorb an aqueous medium is indicated by its Free Swell Capacity orits media uptake ratio for the medium of interest. The term “Free SwellCapacity” refers to the amount, in grams, of a specified aqueous mediumwhich 1 gram of the dried polymer hydrogel can absorb at 37° C. in 60minutes under no load. Preferably, the polymer hydrogel of the inventionhas a Free-Swell Capacity of at least about 50 grams, more preferably ofat least about 70 gram, and most preferably of at least about 100 gramin an aqueous solution containing about 11% simulated gastric fluid(SGF/water=1:8). The procedure for determining the Free-Swell Capacityis set forth below in the examples.

The media uptake ratio (MUR) is another measure of the ability of thepolymer hydrogel to absorb water or a specified aqueous solution at aparticular temperature. The MUR is obtained through swellingmeasurements at equilibrium (using, for example, a Sartorius micro scalewith a sensitivity of 10⁻⁵ g) and it is calculated with the followingformula MUR=W_(s)/W_(d), wherein W_(s) is the weight of the polymerhydrogel after immersion in distilled water or the specified media untilequilibrium is reached, 24 hours unless otherwise specified. Unlessotherwise specified, the MUR is determined at room temperature, or about25° C. W_(d) is the weight of the polymer hydrogel before immersion, thepolymer hydrogel having been previously dried in order to remove anyresidual water.

In a preferred embodiment, the method for preparing a polymer hydrogelof the invention comprises the steps of (a) providing an aqueoussolution consisting essentially of: (a) a cellulose derivate, such ascarboxymethylcellulose or a salt thereof, or hydroxyethylcellulose or acombination thereof, a polycarboxylic acid, such as citric acid, andwater; (b) stirring the aqueous solution; (c) evaporating the free waterfrom the solution to produce a dried polymer/carboxylic acid composite;(d) grinding the dried composite to form composite particles; and (e)heating the composite particles to a temperature of at least about 80°C. or at least about 100° C., thereby cross-linking the cellulosederivative and forming a polymer hydrogel.

In certain embodiments, the product of step (e) is ground to produceparticles and the particles are optionally sieved. This is particularlydesirable in cases in which step (e) causes agglomeration of particlesproduced in step (d). The particles can be sieved to yield a samplecomprising particles within a desired size range. The size of theparticles can, for example, affect the amount of hydrogel that can fitwithin a capsule for an oral dosage form. The particle size also affectsthe rheological properties, such as the elastic modulus, and theswelling kinetics of the hydrogel. In one embodiment, the hydrogelconsists substantially of particles in the size range from 1 μm to 2000μm, preferably from 10 μm to 2000 μm, and more preferably from 100 μm to1000 μm. A sample of hydrogel consists substantially of particles in aspecified size range when the hydrogel is greater than 50% by massparticles in the specified size range. Preferably, the hydrogel is atleast 60%, 70%, 80%, 90% or 95% by mass particles in the specified sizerange.

The cellulose derivative is preferably present in the aqueous solutionat a concentration of 4% or greater, preferably from about 4% to about8%, 5% to about 7%, 5.5% to about 6.5% or about 6% by weight relative tothe weight of the water used to prepare the solution. Preferably thepolycarboxylic acid is present in the solution at a concentration ofabout 0.5% or less, more preferably, about 0.35% or less or about 0.3%or less by weight relative to the weight of the cellulose derivative.Preferably the cellulose derivative is carboxymethylcellulose at aconcentration of about 5% to about 7%, more preferably about 5.5% toabout 6.5% and most preferably about 6% by weight relative to water, andthe polycarboxylic acid is citric acid, at a concentration of about0.15% to about 0.35%, preferably about 0.2% to about 0.35%, 0.15% toabout 0.3% or about 0.3% by weight relative to carboxymethylcellulose.

The pH of the aqueous solution is preferably maintained from about 5 toabout 9, from about 6 to 8, from about 6.5 to about 7.5 or about 5.5 toabout 7.

In one embodiment of the method of the invention, the aqueous solutionis dried to form the dried composite as a sheet, which is ground to formcomposite particles. Preferably the composite particles have a greatestdimension between 10 μm and 1000 μm, more preferably between 100 μm and1000 μm with an average size of between 300 μm and 600 μm. The compositeparticles are optionally sieved to provide particles in a desired sizerange. The composite particles are cross-linked at elevated temperature,preferably 80° C. or higher or 100° C. or higher. In preferredembodiments, the resulting particles are substantially homogeneouslycross-linked. It is believed that cross-linking in a particle shapecreates a preferential tighter cross-linked outer boundary for theparticle that improves the particle's elasticity and still maintainsgood water absorbency capability in the core of the particles.

The time required to cross-link the particles depends upon thecross-linking temperature and the concentration of the polycarboxylicacid. For example, at a citric acid concentration of 0.3% (w/w vs.carboxymethylcellulose) it takes about 2-10 minutes at 180° C. or 2-5hours at 120° C. to cross-link the carboxymethylcellulose. At 80° C. ittakes 4 hours with a citric acid concentration of 2.5% (w/w) or 20 hourswith a citric acid concentration of 1% (w/w).

Steps (b)-(e) of the process can take place in a single operation. Thesolution of step (a) can be, for example, spray dried. That is, thesolution can be sprayed into a chamber to form droplets which are driedand cross-linked by a stream of hot air. In this embodiment, thesolution is fragmented prior to formation of the composite.

In one embodiment, the composite is isolated from the aqueous solutionby substantially drying the aqueous solution, for example, by heating,as described above.

In preferred embodiments, the aqueous solution is placed on a tray, suchas a stainless steel, polypropylene or Teflon tray, prior to isolatingthe composite. This increases the surface area of the solution,facilitating the evaporation of the water. In an embodiment, thesolution is maintained at elevated temperature until it begins to form asolid or semi-solid, for example, with formation of a gel. The gel isoptionally then inverted in the tray, and heating is continued tosubstantial dryness. The heating preferably can be conducted in asuitable oven or vacuum oven.

The composite is granulated, for example by grinding, milling orfragmenting, to form composite particles and the particles aremaintained at elevated temperature, thereby effecting cross-linking andproducing polymer hydrogel particles. Preferably, the cross-linking step(e) is conducted at a temperature of about 80° or greater or about 100°C. or greater, more preferably from about 100° C. to about 160° C., andstill more preferably, about 115° C. to about 125° C., or about 120° C.

In preferred embodiments, the substantially dry composite is ground toform particles of a suitable size. The ground particles are placed on atray, such as a stainless steel tray or placed in a rotating oven. Thisincreases the surface area, facilitating the preferentially surfacecross-linking reaction. In an embodiment, the particles are maintainedat elevated temperature according to step (e) until cross-linking iscomplete. The heating preferably is conducted in a suitable oven orvacuum oven.

The ground particles are optionally sized, for example by sieving, priorto or following the cross-linking step, to obtain particles within adesired size range.

The methods of the invention can further include the steps of purifyingthe polymer hydrogel, for example, by washing the polymer hydrogel in apolar solvent, such as water, a polar organic solvent, for example, analcohol, such as methanol or ethanol, or a combination thereof. Thepolymer hydrogel immersed in the polar solvent swells and releasesimpurities, such as by-products or unreacted citric acid. Water ispreferred as the polar solvent, distilled and/or deionized water isstill more preferred. The volume of water used in this step ispreferably at least the volume to reach the maximum media uptake degreeof the gel, or at least approximately 2- to 20-fold greater than theinitial volume of the swollen gel itself. The polymer hydrogel washingstep may be repeated more than once, optionally changing the polarsolvent employed. For example, the polymer hydrogel can be washed withmethanol or ethanol followed by distilled water, with these two stepsoptionally repeated one or more times.

The polymer hydrogel can further be dried to remove most orsubstantially all water.

In one embodiment, the drying step is carried out by immersing the fullyswollen polymer hydrogel in a cellulose non-solvent, a process known asphase inversion. A “cellulose non-solvent”, as this term is used herein,is a liquid compound which does not dissolve the cellulose derivativeand does not swell the polymer hydrogel, but is preferably miscible withwater. Suitable cellulose non-solvents include, for example, acetone,methanol, ethanol, isopropanol and toluene. Drying the polymer hydrogelby phase inversion provides a final microporous structure which improvesthe absorption properties of the polymer hydrogel by capillarity.Moreover, if the porosity is interconnected or open, i.e. the microporescommunicate with one another, the absorption/desorption kinetics of thegel will be improved as well. When a completely or partially swollen gelis immersed into a nonsolvent, the gel undergoes phase inversion withthe expulsion of water, until the gel precipitates in the form of avitreous solid as white coloured particles. Various rinses in thenon-solvent may be necessary in order to obtain the dried gel in a shortperiod of time. For example, when the swollen polymer hydrogel isimmersed in acetone as the non-solvent, a water/acetone mixture isformed which increases in water content as the polymer hydrogel dries;at a certain acetone/water concentration, for example, about 55% inacetone, water is no longer able to exit from the polymer hydrogel, andthus fresh acetone has to be added to the polymer hydrogel to proceedwith the drying process. Increasing the acetone/water ratio duringdrying increases the rate of drying. Pore dimensions are affected by therate of the drying process and the initial dimensions of the polymerhydrogel particles: larger particles and a faster process tend toincrease the pore dimensions; pore dimensions in the microscale rangeare preferred, as pores in this size range exhibit a strong capillaryeffect, resulting in the higher sorption and water retention capacity.

In other embodiments, the polymer hydrogel is not dried by phaseinversion. In these embodiments, the polymer hydrogel is dried byanother process, such as air drying, vacuum drying, freeze drying or bydrying at elevated temperature, for example, in an oven or vacuum oven.These drying methods can be used alone or in combination. In certainembodiments, these methods are used in combination with the non-solventdrying step described above. For example, the polymer hydrogel can bedried in a non-solvent, followed by air drying, freeze drying, ovendrying, or a combination thereof to eliminate any residual traces ofnonsolvent. Oven drying can be carried out at a temperature of, forexample, approximately 30-45° C. until the water or residual non-solventis completely removed. The washed and dried polymer hydrogel can then beused as is, or can be milled to produce polymer hydrogel particles of adesired size.

In preferred embodiments, the cellulose derivative iscarboxymethylcellulose, more preferably carboxymethylcellulose sodiumsalt. In another embodiment, the cellulose derivative ishydroxyethylcellulose.

In another embodiment, the cellulose derivative is a combination ofcarboxymethylcellulose and hydroxyethylcellulose. The weight ratio ofcarboxymethylcellulose to hydroxyethylcellulose can be from about 1:10to about 10:1. Preferably the weight ratio of carboxymethylcellulose tohydroxyethylcellulose is about 1 or less, more preferably, from about1:5 to about 1:2, more preferably about 1:3.

One particularly preferred embodiment of the method of the inventioncomprises the following steps: Step 1, carboxymethylcellulose sodiumsalt and citric acid are dissolved in purified water to produce asolution essentially consisting of about 5% to about 7%, preferablyabout 6%, carboxymethylcellulose by weight relative to the weight ofwater, and citric acid in an amount of about 0.15% to about 0.35% orabout 0.15% to about 0.30% by weight relative to the weight ofcarboxymethylcellulose; Step 2, maintaining the solution at atemperature from about 40° C. to about 70° C. or 40° C. to about 80° C.,preferably about 70° C., to evaporate the water and form a substantiallydry carboxymethylcellulose/citric acid composite; Step 3, grinding thecomposite to form composite particles; and Step 4, maintaining thecomposite particles at a temperature from about 80° C. to about 150° C.or about 100° C. to about 150° C., preferably, about 120° C., for aperiod of time sufficient to achieve the desired degree of cross-linkingand form the polymer hydrogel. The method can optionally further includeStep 5, washing the polymer hydrogel with purified water; and Step 6,drying the purified polymer hydrogel at elevated temperature.

The present invention also provides polymer hydrogels which can beprepared using the methods of the invention. Such polymer hydrogelscomprise cross-linked carboxymethylcellulose, hydroxyethylcellulose or acombination of carboxymethylcellulose and hydroxyethylcellulose. In apreferred embodiment, the polymer hydrogel consists essentially ofcitric acid cross-linked carboxymethylcellulose.

In another embodiment, the present invention provides polymer hydrogels,including superabsorbent polymer hydrogels, which can be prepared usingthe methods of the invention. The invention includes articles ofmanufacture, pharmaceutical compositions, foods, foodstuffs and medicaldevices, agriculture and horticulture products, personal hygieneproducts which comprise such polymer hydrogels. The invention furtherincludes methods of use of the polymer hydrogels of the invention forthe preparation of foods and the treatment of obesity.

In certain embodiments, polymer hydrogels produced by the methodsdescribed herein form xerogels that have greater density thancarboxymethylcellulose xerogels produced using other methods, whileretaining significant absorption properties.

The methods of the invention produce polymer hydrogels which combineboth physical and chemical cross-linking and which have good mechanicalproperties, long term stability in dry and swollen form and goodretention capacity and biocompatibility. [Demitri et al., Journal ofApplied Polymer Science, Vol. 110, 2453-2460 (2008)] The polymerhydrogels of the invention exhibit good media uptake properties in thefree state, high bulk density, and cost effective production. Further,the polymer hydrogels have rapid media uptake kinetics in body fluids.

In preferred embodiments, the polymer hydrogels of the invention have amedia uptake ratio in distilled water of at least about 20, about 30,about 40, about 50, about 60, about 70, about 80, about 90 or about 100.For example, in certain embodiments, the polymer hydrogels of theinvention have a media uptake ratio in distilled water from about 20 toabout 1000, from about 20 to about 750, from about 20 to about 500, fromabout 20 to about 250, from about 20 to about 100. In certainembodiment, the polymer hydrogels of the invention have a media uptakeratio in distilled water from about 20, 30, 40, 50, 60, 70, 80, 90 or100 to about 120, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000 orgreater, or within any range bounded by any one of these lower limitsand any one of these upper limits.

In certain embodiments, the polymer hydrogels of the invention canabsorb an amount of one or more bodily fluids, such as blood, bloodplasma, urine, intestinal fluid or gastric fluid, which is at least 10,20, 30, 40, 50, 60, 70, 80, 90, or 100 times their dry weight. Theability of the polymer hydrogel to absorb bodily fluids can be testedusing conventional means, including testing with samples of bodilyfluids obtained from one or more subjects or with simulated bodilyfluids, such as simulated urine or gastric fluid. In certain preferredembodiments, the polymer hydrogels can absorb significant amounts of afluid prepared by combining one volume of simulated gastric fluid (SGF)with eight volumes of water. SGF can be prepared using USP TestSolutions procedures which are known in the art. In some embodiments,the polymer hydrogels of the invention have a media uptake ratio of 10,20, 30, 40, 50, 60, 70, 80, 90, 100, or 150 in SGF/water (1:8). In someembodiments the polymer hydrogels of the invention have a media uptakeratio of 10 to 300, from 20 to 250, from 30 to 200, from 50 to 180 orfrom 50 to 150 in SGF/water (1:8). In preferred embodiments the hydrogelhas a media uptake ratio of 50 or greater in SGF/water (1:8).

The polymer hydrogels of the invention include cross-linked polymershaving varying extents of hydration. For example, the polymer hydrogelscan be provided in a state of hydration ranging from a substantially dryor anhydrous state, such as a xerogel or a state in which from about 0%to about 5% or up to about 10% of the polymer hydrogel by weight iswater or an aqueous fluid, to states comprising a substantial amount ofwater or aqueous fluid, including up to a state in which the polymerhydrogel has absorbed a maximum amount of water or an aqueous fluid.

In an embodiment, the polymer hydrogels of the invention are preferablyglassy but amorphous or vitreous materials when in a substantially dryor xerogel form. In an embodiment, the polymer hydrogels of theinvention have a tapped density of greater than about 0.5 g/cm³. Inpreferred embodiments, the tapped density is from about 0.55 to about0.8 g/mL when determined as described in US Pharmacopeia <616>,incorporated herein by reference. In a preferred embodiment, the tappeddensity is about 0.6 g/cm³ or greater, for example, from about 0.6 g/cm³to about 0.8 g/cm³.

A preferred hydrogel of the invention consists of carboxymethylcellulosecross-linked with citric acid. Preferably the hydrogel has a watercontent of less than about 10% by weight, a tapped density of at leastabout 0.6 g/mL, an elastic modulus of at least about 350 Pa, or a mediauptake ratio in SGF/water 1:8 of at least about 50. More preferably thepolymer hydrogel has each of the foregoing properties. In a particularlypreferred embodiment, the polymer hydrogel consists of particles whichare substantially in the size range of 100 μm to 1000 μm. In oneembodiment, at least about 95% of the hydrogel by weight consists ofparticles in the size range of 100 μm to 1000 μm.

The degree of cross-linking (d.c.) of a cross-linked polymer is definedas the number density of junctions joining the polymer chains into apermanent structure. According to this definition the degree ofcross-linking is given by:

$\begin{matrix}{{d.c.} = \frac{\upsilon}{2V}} & ( {{eq}.\mspace{14mu} 1} )\end{matrix}$

where υ/2 is the total number of chemical cross-links and V is the totalvolume of polymer.

The concentration of elastically effective chain elements,ρ_(x)=υ_(e)/V, corresponds to the concentration of all chemicallycross-linked polymer segments (υ/V):

$\begin{matrix}{\rho_{x} = {\frac{\upsilon_{e}}{V} = {\frac{\upsilon}{V} = {{\frac{1}{\overset{\_}{\upsilon}\; {\overset{\_}{M}}_{c}}{d.c.}} = \frac{\upsilon}{2V}}}}} & ( {{eq}.\mspace{14mu} 2} )\end{matrix}$

where υ is the specific volume of the polymer, M _(c) is the averagemolecular weight between cross-links, and υ_(e)/V is the moles ofelastically effective chains per unit volume of network.

The degree of cross-linking can be evaluated by means of uniaxialcompression measurements on the swollen hydrogel. In fact, a swollenhydrogel, when submitted to a uniaxial compressive load, displays adeformational behavior which depends upon the elastic response ofdeformed chains, upon the interaction among fixed charges and upon thefree energy change associated with the release of some amount ofabsorbed water. By making the simplifying assumption that no volumechange occurs upon compression of the swollen hydrogel, Flory derived arelationship between the compressive stress and the compressivedeformation for the case of a swollen cross-linked polymer, based on theassumption of Gaussian statistics and of affine deformation obtaining:

$\begin{matrix}{\sigma = {{{RT}\frac{\upsilon_{e}}{V_{0}}\varphi_{2,r}^{2/3}{\varphi_{2,s}^{1/3}( {\alpha - \frac{1}{\alpha^{2}}} )}} = {G( {\alpha - \frac{1}{\alpha^{2}}} )}}} & ( {{eq}.\mspace{14mu} 3} )\end{matrix}$

where σ=F/A₀ is the uniaxial compressive stress (where F is the tractionforce and A₀ is the initial area of swollen sample cross-section),α=L/L_(i) with L, the actual thickness of the compressed swollen sampleand L_(i), the initial thickness of the swollen sample, R, the universalgas constant, T, the absolute temperature, φ_(2,s), the polymer volumefraction in the swollen state under compression which is assumed to beequal to the value for the undeformed swollen gel, υ_(e)/V₀, the molesof elastically effective chains per cm³ of dry polymer network and G isthe shear modulus of the swollen network. Example 5 describes thedetermination of the degree of cross-linking of samples of citric acidcross-linked CMC prepared using same concentrations of CMC and differentamounts of citric acid. In certain embodiments in which a lowerconcentrations of citric acid is used, for example, less than about 0.5%or 0.4% citric acid by weight relative to carboxymethylcellulose, afraction of the carboxymethylcellulose is not involved in cross-linkednetwork formation and can be removed by washing from the hydrogelproduct.

The hydrogels of the invention preferably have a crosslinked and singlybonded citric acid to carboxymethylcellulose ratio of 0.05% to 1% wt/wtand more preferably a ratio of 0.1% to 0.4% wt/wt. Still morepreferably, the crosslinked and singly bonded citric acid tocarboxymethylcellulose ratio is 0.225% to 0.375% wt/wt.

The hydrogels of the invention preferably have a degree of cross-linkingfrom about 2.5×10⁻⁵ mol/cm³ to about 5×10⁻⁵ mol/cm³, more preferablyfrom about 4×10⁻⁵ mol/cm³ to about 5×10⁻⁵ mol/cm³.

The polymer hydrogels of the invention can be used in methods fortreating obesity, reducing food or calorie intake or achieving ormaintaining satiety. Hydrogels of the invention can also be used toimprove glycemic control and to treat or prevent diabetes. The methodscomprise the step of administering an effective amount of a polymerhydrogel of the invention to the stomach of a subject, preferably byoral administration, for example, by causing the subject, such as amammal, including a human, to swallow the polymer hydrogel, optionallyin combination with ingestion of a volume of water. Upon contactingwater or aqueous stomach contents, the polymer hydrogel swells andoccupies stomach volume decreasing the capacity of the stomach for foodand/or the rate of food absorption. When ingested in combination withfood, the polymer hydrogel increases the volume of the food boluswithout adding to the calorie content of the food. The polymer hydrogelcan be ingested by the subject prior to eating or in combination withfood, for example, as a mixture of the polymer hydrogel with food.

The polymer hydrogel can be ingested alone, in a mixture with liquid ordry food or as a component of a food or edible matrix, in a dry,partially swollen or fully swollen state, but is preferably ingested ina state of hydration which is significantly below its fluid capacity,more preferably the polymer hydrogel is ingested in a substantiallyanhydrous state, that is, about 10% or less water by weight. The polymerhydrogel can be formulated for oral administration in a capsule, sachetor tablet or suspension. When administered in a substantially anhydrousform, the volume of the stomach taken up by the polymer hydrogel will besignificantly greater than the volume of the polymer hydrogel ingestedby the subject. The polymer hydrogels of the invention can also take upvolume and/or exert pressure on the wall of the small intestine bymoving from the stomach into the small intestine and media uptake.Preferably, the polymer hydrogel will remain swollen in the smallintestine for a period of time sufficient to inhibit the intake of foodby the subject, before shrinking sufficiently for excretion from thebody. The time sufficient to inhibit the intake of food by the subjectwill generally be the time required for the subject to eat and for theingested food to pass through the small intestine; Such shrinking canoccur, for example, by degradation through loss of cross-links,releasing fluid and decreasing in volume sufficiently for excretion fromthe body. A schematic depicting the theoretical behaviour of such ahydrogel as it passes through the gastrointestinal tract is set forth inFIG. 2.

The polymer hydrogels of the invention preferably exhibit pH-dependentmedia uptake, with greater media uptake observed at higher pH than atlower pH. Thus, such a polymer will not swell significantly in thestomach unless food and/or water is present to raise the pH of thestomach contents and will move into the small intestine. When ingestedwith food, the polymer hydrogel preferably swells initially in thestomach, shrinks when the stomach is emptied of food and the pH dropsand then moves from the stomach to the small intestine. In the higher pHenvironment of the small intestine the polymer hydrogel will swellagain, taking up volume in the small intestine and/or exerting pressureon the wall of the small intestine.

The polymer hydrogel can optionally be administered in combination witha pH modifying agent, which is an agent which alters the pH of themicroenvironment of the polymer hydrogel, thereby modifying its abilityto absorb fluids. For example, for polymer hydrogels comprising ananionic polymer, agents which increase the pH of the microenvironmentcan increase the swellability of the polymer hydrogel. Suitable pHmodifying agents for use with the polymer hydrogels of the inventioninclude buffering agents, H₂ blockers, proton pump inhibitors, antacids,proteins, nutritional shakes, and combinations thereof. Suitablebuffering agents and antacids include ammonium bicarbonate, sodiumbicarbonate, calcium carbonate, calcium hydroxide, aluminium hydroxide,aluminium carbonate, magnesium carbonate, magnesium hydroxide, potassiumbicarbonate, potassium carbonate, potassium hydroxide, sodium carbonate,sodium hydroxide and combinations thereof. Suitable H₂ blockers includecimetidine, ranitidine, famotidine, nizatidine and combinations thereof.Suitable proton pump inhibitors include omeprazole, lansoprazole,esorneprazole, pantoprazole, abeprazole, and combinations thereof.

The polymer hydrogel of the invention can be administered to the subjectin the form of a tablet or a capsule or other formulation suitable fororal administration. The tablet or capsule can further include one ormore additional agents, such as a pH modifying agent, and/or apharmaceutically acceptable carrier or excipient. The polymer hydrogelcan also be administered as a component of a food or a beverage, such asis described in WO 2010/059725, incorporated herein by reference in itsentirety.

In one embodiment, the present invention provides a pharmaceuticalcomposition comprising a polymer hydrogel of the invention. Thepharmaceutical composition can comprise the polymer hydrogel as anactive agent, optionally in combination with a pharmaceuticallyacceptable excipient or carrier. For example, the pharmaceuticalcomposition can be intended for oral administration to treat obesity,provide enhanced satiety, improve glycemic control, treat or preventdiabetes or aid in weight management. In another embodiment, thepharmaceutical composition comprises the polymer hydrogel in combinationwith another active agent. The polymer hydrogel can serve as a matrix,for example, for sustained release of the active agent.

The scope of the present invention includes the use of the polymerhydrogels obtainable by the method of the invention as an absorbentmaterial in products which are capable of absorbing water and/or aqueoussolutions and/or which are capable of media uptake when brought intocontact with water and/or an aqueous solution. The polymer hydrogels ofthe present invention may be used as absorbent materials in thefollowing fields, which are provided as non-limiting examples: dietarysupplements (for example, as the bulking agents in dietary supplementsfor hypocaloric diets capable of conferring a sensation of lastingsatiety being retained into the stomach for a limited period of time, oras water and low molecular weight compounds supplements, such as mineralsalts or vitamins, to be included into drinks in a dry or swollen form);in agricultural products, for example, in devices for the controlledrelease of water and/or nutrients and/or phytochemicals, particularlyfor cultivation in arid, deserted areas and in all cases where it is notpossible to carry out frequent irrigation; such products, mixed in a dryform with the soil in the areas surrounding the plant roots, absorbwater during irrigation and are capable of retaining it, releasing itslowly in certain cases, together with the nutrients and phytochemicalsuseful for cultivation; in personal hygiene and household absorbentproducts, such as, for example, as the absorbent core in diapers,sanitary napkins and the like; in toys and devices, such as for examplein products which are capable of significantly changing their size oncebrought into contact with water or an aqueous solution; in thebiomedical field, for example, in biomedical and/or medical devices suchas absorbent dressings for the treatment of highly exudative wounds,such as ulcers and/or burns, or in slow-release polymeric films suitableto slowly release liquids adapted for use in ophthalmology; in the bodyfluid management field, for example, for controlling the amount ofliquids in an organism, for example in products capable of promoting theelimination of fluids from the body, such as, for example, in the caseof edema, CHF (congestive heart failure), dialysis; and in home cleaningproducts.

The above-mentioned products, containing a polymer hydrogel of thepresent invention as the absorbent material, also fall within the scopeof the invention.

The invention further includes the use of any of the polymer hydrogelsof the invention in medicine. Such use includes the use of a polymerhydrogel in the preparation of a medicament for the treatment of obesityor any medical disorder or disease in which calorie restriction has atherapeutic, palliative or prophylactic benefit.

EXEMPLIFICATION Example 1 Preparation of Citric Acid Cross-LinkedCarboxymethylcellulose

Materials NaCMC E&V, catalog number 72537 - 7H3SXF Citric Acid Sigma,catalog number 43309268 Purified water Chimica D'Agostino (Bari - Italy)

Method

Purified water (10 kg) was added to a 10 liter Hobart mixer and agitatedat 30 rpm. Citric acid (1.8 g) was added to the water and dissolved.NaCMC (600 g) was then added to the solution and the resulting mixturewas agitated at room temperature at 60 rpm for 90 minutes and then at 30rpm for 15 hours. The resulting solution was added to 10 stainless steeltrays (1.030 kg solution per tray). The trays were placed in a SalvisThermocenter TC240 oven at 45° C. for 24 hours. The trays were removedfrom the oven, the contents were inverted and the trays were placed backin the oven and maintained at 45° C. for 30 hours. After the desiccationthe material was ground by means of a cutting mill (Retsch cutting mill)equipped with a 1 mm screen. The granulated material was then spread onthe trays and cross-linked in the Salvis Thermocenter TC240 oven at 120°C. for 4 hours. The cross-linked polymer hydrogel thus obtained waswashed with purified water for 24 hours to remove the unreacted reagents(by changing the washing solution 4 times). The washing stage allows themedia uptake of the cross-linked polymer by increasing the relaxation ofthe network thus increasing the media uptake capacity of the finalmaterial obtained after a further desiccation step. After the washingthe material was placed on trays and into the oven at 45° C. to dry. Thedry material was then ground and sieved to a particle size from 0.1 mmto 1 mm.

Media Uptake Ratio (MUR)

For this example, equilibrium media uptake measurements for all thesamples were carried out in a mixture of simulated gastric fluid (SGF)and water (1:8 v/v) using a Sartorius microbalance (10⁻⁵ sensitivity).The media uptake ratio was measured by weighing samples (sieved between400 μm and 600 μm) before and after their immersion in the SGF/water(1:8)

The results indicated that the media uptake ratio (MUR) of the sampleincreases with the time and reaches its maximum value after 30 minutes.The media uptake ratio for each tested sample is presented in Table 1below.

TABLE 1 time MUR (h) (g/g) 0.25 21 0.5 37 0.75 58 1 67 2 69

Discussion

The data show dependence of the absorption capacity with time up to 30min. No relevant differences are noted between the samples at 1 h and 2h. This is a typical behavior exhibited by superabsorbent hydrogels andis due to the Donnan Effect. The presence of fixed charges on thepolymeric backbone, typical of polyelectrolyte gels, leads tosignificant rapid swelling of the polymer in water. This behavior is dueto a Donnan equilibrium established between gel and the externalsolution, whose ionic strength strongly affects the swelling degree. Inthis case, the polymer hydrogel can be considered as a semipermeablemembrane that allows the water to enter in order to dilute the fixedcharges linked to the polymer backbones. Since the charges are fixed andthey cannot move in the opposite direction, more water is necessary toreach the equilibrium, thus allowing the swelling of the polymerhydrogel.

The data presented here and in Example 8 support the idea that asignificant effect of washing is the removal of unreacted polymer fromthe hydrogel. Such unbreacted polymer can serve as a molecular spacerduring the cross-linking process, serving to increase the distancebetween cross-linking sites. It is also believed that washing stretchesthe cross-linked polymer network, increasing polymer mobility andabsorption kinetics.

Example 2 Study of the Effect of Washing Procedure on the Properties ofCitric Acid Cross-Linked Carboxymethylcellulose

The samples were prepared according to the procedure described inExample 1 with the exception of the washing procedure. In thispreparation the sample was divided into 4 mparts, each of which waswashed with distilled water 1, 2, 3 or 4 times. The first 3 washes wereperformed for 3 hours and the last one for 14 hours. The yield of theprocess was calculated as follows:

Y%=W _(hydrogel) /W _(cmc)

where the W_(hydrogel) is the weight of dry material obtained after theprocess and W_(cmc) is the weight of the carboxymethylcellulose in thestarting mixture. The media uptake ratio of each washed sample wasdetermined in SGF/water (1:8) and the results are set forth in Table 2.

TABLE 2 Number of washings Yield MUR (g/g) 0 91% 17 1 81% 32 2 69% 35 362% 36 4 59% 69

Discussion

The results indicate that the media uptake ratio increases with thenumber of washes. This is due to a reduction of the degree ofcross-linking. The hydrogel network includes both physical entanglementsand chemical cross-links. Without being limited by theory, it isbelieved that physical entanglements are reduced by washing due to theelectrostatic repulsion between the chains and to the increased mobilityof these chains due to the increased volume of the hydrogel. As a directconsequence of this enhanced absorption capacity, the yield of theprocess decreases. This is believed to be due to the solubilization ofunreacted carboxymethylcellulose during the washing which decreases thefinal weight of the product. The reduction in yield may also relate tolosses from the additional manipulation of the material required by theadditional washing steps.

Example 3 Effect of Cross-Linking Time on the Properties of Citric AcidCross-Linked Carboxymethylcellulose Method

Purified water (10 kg) was added to a 10 liter Hobart mixer and agitatedat 30 rpm. Citric acid (1.8 g) was added to the water and dissolved.NaCMC (600 g) was then added to the solution and the resulting mixturewas agitated at room temperature at 60 rpm for 90 minutes and then at 30rpm for 15 hours. The resulting solution was added to 10 stainless steeltrays (1.030 kg solution per tray). The trays were placed in a SalvisThermocenter TC240 oven at 45° C. for 24 hours. The trays were removedfrom the oven, the contents were inverted and the trays were placed backin the oven and maintained at 45° C. for 30 hours. After drying, part ofthe material was ground by means of a cutting mill (Retsch cutting mill)equipped with 1 mm screen, and one sample was stored in sheet form forcontrol purposes (sample C). The remaining material was then sieved anddivided into 2 parts according to Table 3.

TABLE 3 Sample Particle size range (μm) A 500-1000 B 100-500 C Sheet(infinite particle)

Samples A, B and C were each divided into three parts. These portions ofsamples A, B and C and were then spread on the tray and cross-linked inthe Salvis Thermocenter TC240 oven at 120° C. for 2, 3 or 4 hours. Theresulting cross-linked polymer hydrogel was washed with distilled waterfor 24 hours in order to remove the unreacted reagents (by changing thewashing solution 4 times). After washing, the material was placed ontrays into the oven at 45° C. until complete dessication. The drymaterial was then ground and sieved between 100 μm and 1000 μm particlesize.

Discussion

The media uptake ratio of these samples in SGF/water (1:8) is presentedin Table 4.

TABLE 4 Cross-linking Sample Time (h) MUR (g/g) A 2 80 A 3 74 A 4 58 B 288 B 3 83 B 4 69 C 2 95 C 3 86 C 4 83It is evident that media uptake capacity decreases with increasingcross-linking time. However, the main particle size is not the mostdominant parameter affecting media uptake.

Example 4 Effect of Cross-Linking Particle Size on Properties of CitricAcid Cross-Linked Carboxymethylcellulose Method

Purified water (10 kg) was added to a 10 liter Hobart mixer and agitatedat 30 rpm. Citric acid (1.8 g) was added to the water and dissolved.NaCMC (600 g) was then added to the solution and the resulting mixturewas agitated at room temperature at 60 rpm for 90 minutes and then at 30rpm for 15 hours. The resulting solution was added to 10 stainless steeltrays (1.030 kg solution per tray). The trays were placed in a SalvisThermocenter TC240 oven at 45° C. for 24 hours. The trays were removedfrom the oven, the contents were inverted and the trays were placed backin the oven and maintained at 45° C. for 30 hours. After the desiccationpart of the material was ground by means of a cutting mill (Retsch,cutting mill) equipped with 1 mm screen, and one small sample was storedin sheet form for control purposes (sample D). The ground material wasthen sieved and divided into 3 parts according to Table 5.

TABLE 5 Sample ID Particle size range (μm) A 1000-3000 B  500-1000 C 100-500 D Sheet (infinite particle)

Samples A-D were then spread on the trays and cross-linked in the SalvisThermocenter TC240 oven at 120° C. for 4 hours. The cross-linked polymerhydrogels thus obtained were washed for 24 hours with distilled water toremove the unreacted reagents (by changing the washing solution 4times). After washing, the material was spread on the trays and placedin the oven at 45° C. to dry. The dry material was then ground andsieved to a particle size from 100 μm and 1000 μm.

Discussion

The media uptake ratio (MUR) of Samples A-D in SGF:water (1:8) ispresented in Table 6.

TABLE 6 Sample Media Uptake Ratio (g/g) A 64 B 63 C 55 D 80Samples A, B and C had negligible differences in media uptake (around15% which can be attributed to experimental error). Sample D, thecross-linked sheet, demonstrated an increased media uptake capacity.

Conclusions:

As demonstrated by the media uptake ratio which is directly related tothe cross linking density/efficiency, the samples which werecross-linked as particles demonstrated greater cross-linking efficiencydue to their homogeneity. The sheet had its top side cross linked whileits back side was hardly cross-linked, resulting in greater media uptake(over 35%).

Example 5 Determination of Degree of Cross-Linking of Citric AcidCross-Linked Carboxymethyl Cellulose Method:

A disc of swollen hydrogel is tested through an uniaxial-compressiveload by means of rotational rheometer (ARES Rheometric Scientific)equipped with a parallel plate tools. The discs were prepared by soakingfor 24 h a dry crosslinked sheet of material in distilled water. Thenthe swollen sheet is cut in round disks of 25 mm in diameter through aPE punch. The disk is placed on the parallel plates of the rheometer forthe compressive test with a compressive rate of 0.001 mm/s. Assumingthat there are no changes in the volume of the sample during thecompression test, Flory derived a relationship between the compressivestress and the compressive deformation for the case of a swollencrosslinked polymer, based on the assumption of Gaussian statistics foran affine deformation (eq. 3).

Although this approach is oversimplified, due to the assumption ofconstant volume (actually some water is squeezed out of the swollensample as a result of compression), it can be used to understand geldeformation (α=(l−l₀)/l₀, were l₀ and l are the highs of the startingsample before and after compression respectively) and behavior underuniaxial compression in the case of small deformations (α−1) and can beused for the evaluation of the ratio υ/V₀ and of ρ_(x) (see eq. 3).

The deviation from Gaussian statistics at large deformations can betaken into account by using a phenomenological expression to describethe behavior of a swollen crosslinked network submitted to uniaxialextension. This expression can be derived from the expression ofMooney-Rivlin strain energy function for swollen rubbers which accountsfor both the deformation due to swelling and the deformation due tocompression. Making the assumption of incompressibility, the followingexpression relating the uniaxial stress s (referred to thecross-sectional area of undeformed swollen sample) to the extensionratio, a, can be derived:

$\begin{matrix}{\sigma = {2( {K_{1} + \frac{K_{2}}{\alpha}} )( {\alpha - \frac{1}{\alpha^{2}}} )}} & ( {{eq}.\mspace{14mu} 4} )\end{matrix}$

where σ has the same definition as in Eq. (3) and the values of K₁ andK₂ are proportional to the swelling ratio of the sample. According toEq. (4), a plot of σ(α−1/α²)⁻¹ vs. 1/α based on experimental data shouldbe linear. A plot of σ (Pa) versus l₀−l (μ) from a typical test ispresented in FIG. 3. A plot of −σ(α−1/α²)⁻¹ versus 1/α from a typicalexperiment is set forth in FIG. 4.

The slope of linear fit of the experimental data gives the value of G tobe used in the eq. 3. Using this value it is possible to evaluate thedegree of crosslinking of the swollen hydrogel network. Measurementshave been performed at different CMC concentrations and differentamounts of citric acid, and results are reported in FIG. 5. Five sampleswere evaluated for each concentration and the plot in FIG. 5 is theaverage obtained excluding the both the higher and the lower value ofthe measurement obtained. The results show that the degree ofcrosslinking increases with increasing the citric acid concentration,which is in agreement with the assumption that the citric acid act as achemical crosslinker for the polymer network, by means of a doubleanidrification/double esterification mechanism.

An evaluation of the degree of crosslinking have been also performed asa function of the polymer (CMC) concentration in the starting solution,as reported in FIG. 6, at a fixed citric acid concentration (0.3% wt/wtrelative to CMC).

It can be observed that the degree of crosslinking increases byincreasing the polymer concentration, at fixed crosslinkerconcentration, and this correlation is not linear. This occurs becausethe stabilization reaction occurs in a shrinked state, as describedabove. Thus, at increased concentration of polymer, the average distancebetween two adjacent polymer molecules is lower, and covalent bonds arecreated among molecules that potentially can be positioned at muchhigher distance once the polymer network is swollen, thus preventing thematerial to swell to its full potential, and increasing the effectivedegree of crosslinking, being the average distance between to subsequentcrosslinking sites lower. The non linear correlation is thus explainedas the variation of the average distance between polymer molecules isrelated to volumetric variation of the solid portion of the reactivemass.

According to what is stated above, it is expected that the media uptakecapacity of the hydrogel is dependent on the polymer (CMC) concentrationin the starting solution. This is confirmed by the graph in FIG. 7,where the media uptake ratio of the hydrogel is reported as a functionof the polymer concentration in the starting solution, at a fixed (0.3%of the polymer) concentration of the crosslinker (citric acid). The dataset forth in FIG. 7 were obtained on the same samples used for thecompression measurements. These disc-shaped samples were placed indeonized water for 24 hours and then dried at 45° C. for 48 hours. Themedia uptake ratio was calculated using the weight before and afterdrying.

Table 7 compares properties of the material of this example prepared ata citric acid concentration of 0.3% by weight relative tocarboxymethylcellulose and material prepared as described in Example 10.

TABLE 7 MUR in G′ at G″ at SGF/Water 10 rad/s 10 rad/s η at 0.5 rad/sSAMPLE 1:8 [Pa] [Pa] [Pa * s] Example 5 27.46 4361.50 1877.5 905.00Prepared according to 72.15 1093.53 153.38 319.99 Example 10

It is observed that, except for the very low concentration of 0.25% ofCMC in the starting solution, where fully chemical stabilization of thepolymer network is not expected, the media uptake ratio decreases withthe amount of CMC. This reduction is due to an increased value of theelastic component due to an higher value of the degree of crosslinking.This suggests a proper correlation of the CMC concentration used duringthe synthesis as a function of the crosslinker concentration, with theaim to find a range of values of the reactants concentration able toprovide a superabsorbent behaviour of the polymer in conditions closestto the actual use of the material (water, water solutions,gastro-intestinal fluids, etc.).

Example 6 Comparison of Structural Properties of Hydrogels PreparedUsing Different Methods

In this example, properties of hydrogels prepared using the methods ofthe invention were compared with those of hydrogels prepared as setforth in WO 01/87365 example IX, samples 202 and 203.

Preparation of Samples A and B

Materials: Sodium carboxymethyl cellulose—Aqualon 7HOF, pharmaceuticalgrade

-   -   Citric Acid—Carlo Erba, USP grade

Samples A and B were prepared as described for samples 202 and 203 ofExample IX of WO 01/87365. For both samples, a solution of 2% (w/wwater) sodium carboxymethyl cellulose and citric acid (0.6% (w/w CMC)for Sample A; 1.0% (w/w CMC) for Sample B) was prepared in water bymixing until complete dissolution occurred. The solutions were pouredinto polypropylene trays and maintained at 95° C. for 16 hours.Thereafter, the dry sheets were ground using a Quadro Model U5 CoMilland the resulting powder was sieved. The fraction between 100 and 1000um was collected.

Preparation of Sample C

Materials: Sodium carboxymethyl cellulose—Aqualon 7H3SXF, pharmaceuticalgrade

-   -   Citric Acid—Carlo Erba, USP grade

An aqueous solution of 6% (w/w water) sodium carboxymethyl cellulose andcitric acid (0.3% w/w CMC) was prepared and mixed for 12 hours. Thesolution was then poured into a polypropylene tray and maintained at 45°C. for 12 hours. The residue was ground with a mill to provide a finepowder with a particle size distribution of 100-1000 μm. The powder wasmaintained at 120° C. for 5 hours, and then washed three times withdeionized water at a water:powder ratio of 80:1 (v/v) with constantmixing. The powder was then dried for 48 h at 45° C. Thereafter, the drymaterial was round again using a Quadro Model U5 CoMill and the powderwas sieved and the fraction between 100 and 1000 um was collected.

Preparation of Sample D

Materials: Sodium carboxymethyl cellulose—Aqualon 7H3SXF, pharmaceuticalgrade

-   -   Citric Acid—Carlo Erba, USP grade    -   Sorbitol (ADEA Srl—food grade)

An aqueous solution of 2% (w/w water) sodium carboxymethyl cellulose,sorbitol (4% wt/wt water) and citric acid (1% w/w CMC) was prepared andmixed for 12 hours. The solution was then poured into a polypropylenetray and maintained at 45° C. for 48 hours. The residue was maintainedat 80° C. for 12 hours, and then ground and washed three times withdeionized water at a water:powder ratio of 80:1 (v/v) with constantmixing. The powder was then dried for 48 h at 45° C. The material waspoured into a glass beaker with acetone for 3 desiccation steps of 2hours each: 1/1, 1/1, 1/10 material to acetone ratio for each steprespectively Thereafter, the dry material was ground again using aQuadro Model U5 CoMill. The powder was sieved and the fraction between100 and 1000 um was collected.

Characterization of Hydrogels NMR Analysis

Approximately 0.02 g of each hydrogel sample was transferred into aglass vial and D₂O (2 mL) at room temperature. The swollen hydrogelswere allowed to stand for at least 24 h before being transferred to theNMR rotor (vide ultra).

HR-MAS NMR

¹H NMR spectra of hydrogel systems were recorded on a Bruker Avancespectrometer operating at 500 MHz proton frequency, equipped with a dual¹H/¹³C HR MAS (High Resolution Magic Angle Spinning) probe-head forsemi-solid samples (Lippens, G. et al., M. Curr. Org. Chem. 1999, 3,147). The basic principle of this approach can be summarized as follows.The fast rotation of the sample at the so called magic-angle (54.7° withrespect to the z-direction of the stray field of the NMR magnet)averages the dipole-dipole interactions and susceptibility distortions,causing a dramatic improvement of spectral resolution (Viel, S.;Ziarelli, F.; Caldarelli, S., Proc. Natl. Acad. Sci. U.S.A. 2003, 100,9696). The hydrogels prepared as described above were transferred into a4 mm ZrO₂ rotor containing a volume of about 50 μL. All of the ¹Hspectra were acquired with a spinning rate of 4 kHz to eliminate thedipolar contribution.

T2 filtration was achieved by using the classicCarr-Purcell-Meiboom-Gill spin-echo pulse sequence with 1 ms echo-time.

The water self-diffusion coefficient was measured by Diffusion Orderedcorrelation SpectroscopY (DOSY) experiments, based on the pulsed fieldgradient spin-echo (PGSE) approach. A pulsed gradient unit capable ofproducing magnetic field pulse gradients in the z-direction up to 53G·cm⁻¹ was used.

HRMAS-NMR: Pulse-Collect with Water Presaturation

The spectra of the hydrogel samples C and D are shown in FIG. 8. Thecorresponding spectra of samples A and B are set forth in FIG. 9. Thespectra were acquired by using the presaturation of the intense signaldue to the residual water 4.76 ppm. The spectra represent a fingerprintof the polymeric gel. The peaks labelled with * disappeared after somedays. They can thus be due to some metastable state evolving toequilibrium with time. A striking feature characterize these samples. Inthe spectra of samples A and B, the AB quartet of sodium citrate,indicated in the spectra as “SC”, is present. This means these hydrogelshave a quantity of free sodium citrate. In order to double-check theassignment, the spectra of pure sodium citrate in a reference standardhydrogel preparation (agarose-carbomer) and in D₂O solution are alsoshown (first and second traces from top, respectively). It is importantto stress that the signal of free citrate is not present in samples Cand D (vide ultra).

HRMAS-NMR: T2 Filtering

In the general case of cross-linked, swellable polymers, the acquisitionof the NMR signal after T2 filtration allows the extraction ofmagnetization arising from:

-   -   a. the low molecular weight fractions of a polydisperse polymer;    -   b. The part of the backbone of the polymer with higher mobility;    -   c. any dangling chains or groups with faster motion than the        backbone; and    -   d. any small molecule absorbed, adsorbed, entrapped or        encapsulated within the polymeric matrix.        For samples A, B and C, the spectral signals which survive after        T2 filtration are likely due to factors b and d.

FIG. 10 shows the superimposition of the spectra of samples C and Dcollected with T2 filtering. As a general comment, sample C shows somepeaks that are probably due to metastable states. The peaks labelledwith * indeed vanish after the sample is allowed to stand for 48 h. Thespectrum of sample D shows sharp peaks in the spectral region of theglucose backbone, indicating similar chain dynamics. The interpretationof sample C is less clear, probably for the reasons mentioned above. T2filtered HRMAS NMR spectra confirm that samples C and D do not containfree citrate. The signal due to sodium citrate in the reference gel isshown in the top trace of FIG. 10 (oval frame). The arrows indicatewhere in the spectra of these samples such signals would be if present.

The results for samples A and B are shown in FIG. 10. The signal is, ingeneral, less abundant than that observed in samples C and D, indicatinga slower chain dynamics. Differently from what observed in samples C andD, samples A and B do contain detectable amounts of free citrate. Thecorresponding NMR signals are in oval frames in FIG. 11.

DOSY HRMAS-NMR

The self-diffusion coefficient D of the water molecules inside thehydrogels was also measured. In some cases water molecules may interactstrongly with the polymeric matrix, thus giving rise to different typesof water according to the transport behavior: bulk water and boundwater. If the two types of water are in fast exchange on the NMRtime-scale, the observed D is the population-weighted average of Dboundand Dbulk, whereas if the bound and free water are in slow exchange onthe NMR timescale, two different NMR signals are observed and the Dboundand Dbulk coefficients can be measured (Mele, A.; Castiglione, F. et alJ. Incl. Phenom. Macrocyc. Chem., 2011, 69, 403-409).

In the present study, the experimental D measured for each sample fallsin the range 2.3 to 2.6×10⁻⁹ m²s⁻¹. In view of the uncertaintyassociated with the measurement, it can be concluded that the waterinside the hydrogels shows a self-diffusion coefficient in goodagreement with that of bulk water reported in the literature at the sametemperature (Holz, M.; Heil, S. R.; Sacco, A. Phys. Chem. Chem. Phys.,2000, 2, 4740-4742). Therefore, no specific water/polymer interactionscan be accounted for in these systems.

Conclusions

HRMAS-NMR methods are suitable for a fingerprint characterization ofhydrogels made of citric acid cross-linked CMC polymeric hydrogels.Sample C does not show detectable traces of free citric acid/citrate,whereas samples A and B clearly and unambiguously show the NMR signal ofcitrate. This confirms that in samples A and B the doubleanhydrification/double esterification reaction is inhibited by thepresence of water during the crosslinking stage of these samples, whichis associated with the absence of the desiccation and grinding stepsbefore crosslinking.

Sample C shows faster chain dynamics compared to samples A and B. Thisis a consequence of the absence of any washing and further desiccationsteps in the synthesis of these samples. This is related to the observedfaster absorption of water by sample C.

Water molecules inside the polymeric matrices show transport propertiesclose to free, bulk water, thus indicating that no specific interactionsof the water molecules with the polymer are present in these hydrogels.

The data suggest that samples A and B are physically crosslinked in astable, compact network compared to the chemically stabilized, lowcrosslinked and highly mobile network structure of sample C. As shownbelow, this results in higher swelling capacity and faster swellingkinetics of sample C compared to samples A and B.

Swelling Kinetics

Each of the samples provided a uniform, transparent, highly viscoushydrogel upon treatment with deuterated water, as described above. Bothsamples B and C showed a decreased capability to absorb water comparedto sample A (0.02 g of samples/1 mL water).

During the sample preparation, a different swelling behavior of sample Ccompared to samples A and B was observed. Sample C provided a dense,viscous hydrogel almost immediately after the addition of water, whereassamples A and B required much longer time to reach a single phase,homogeneous gel state.

Equilibrium Swelling

Media uptake measurements were performed on samples in the powder form(100-1000 microns particle size distribution) soaked for 30 minutes indifferent media (DI water, NaCl 0.9%, SGF/water 1:8). SGF is a SimulatedGastric Fluid. One liter of SGF is obtained by mixing 7 ml HCl 37% with2 g NaCl and 993 ml of water. After NaCl dissolution 3.2 g of pepsin areadded. Results for three aliquots of each sample are reported in Tables8-10.

TABLE 8 Sample A Media uptake ratio Media uptake ratio Media uptakeratio in deionized water in 9% NaCl in SGF/Water 1:8 1 39.35 21.51 30.32 44.84 20.66 32 3 41.66 23.33 30.7 Average 41.95 21.83 31.00

TABLE 9 Sample B Media uptake Media uptake ratio, deionized Media uptakeratio, SGF/Water water ratio, 9% NaCl 1:8 1 23.41 14.6 21.6 2 23.3515.09 20.65 3 23.25 15.53 23.6 Average 23.34 15.07 21.95

TABLE 10 Sample C Media uptake Media uptake ratio, deionized Mediauptake ratio, SGF/Water water ratio, 9% NaCl 1:8 1 133.9 57.2 70 2142.23 54.81 72.54 3 139.24 58.92 73.91 Average 138.46 56.98 72.15

The media uptake ratio in all three media is significantly greater forsample C than for samples A and B. This is due to the differences inmolecular structure discussed in the previous chapter, and in particularto the difference in the mechanism of stabilization of themacromolecular network and the increased mobility of the macromolecularmoieties. These properties are in turn associated with the differentsynthesis processes used for these samples and, in particular, thedesiccation, grinding, washing and second drying processes included inthe synthesis of sample C.

Mechanical Properties

The storage modulus (G′), the loss modulus (G″) and the viscosity of thesamples were evaluated after soaking three aliquots of each sample inSGF/water 1:8 for 30 minutes. A rheometer equipped with parallel plates(25 mm diameter) was used for the analyses. The frequency range wasfixed between 1 rad/s to 50 rad/s and the strain was fixed at 0.5%(value in which the parameters present a linear behavior in a strainsweep test: fixed frequency at 1 Hz and variable strain). The values(G′-G″-viscosity) were registered at 10 rad/s. The results for samplesA, B and C are set forth in Tables 11-13, respectively.

TABLE 11 Sample A G′ at 10 rad/s η at 0.5 rad/s [Pa] G″ at 10 rad/s [Pa][Pa * s] 1 3252.83 704.47 279.68 2 2371.82 551.42 271.76 3 2585.11594.41 283.98 Average 2736.59 616.77 278.47

TABLE 12 Sample B G′ at 10 rad/s η at 0.5 rad/s [Pa] G″ at 10 rad/s [Pa][Pa * s] 1 4055.94 998.83 320.17 2 4425.04 1004.82 287.41 3 2654.34702.95 279.89 Average 3711.77 902.20 295.82

TABLE 13 Sample C G′ at 10 rad/s η at 0.5 rad/s [Pa] G″ at 10 rad/s [Pa][Pa * s] 1 1176.55 158.67 337.28 2 1100 156.88 322.89 3 1004.05 144.58299.81 Average 1093.53 153.38 319.99

Larger values of both conservative (G′) and dissipative (G″) moduli arein accordance with the lower swelling capacity of samples A and B. Dueto absence of a washing step following cross-linking, a more compact,highly entangled and strongly stabilized structure with secondarybonding is expected for these samples compared to sample C. This resultsin a larger chemical constraint and, in turn, to a lower swellingcapacity of samples A and B. The lower chemical mobility associated withthe different structure of these samples is also responsible for theirgreater mechanical properties.

Conclusions

Differences in synthesis procedures between samples A and B and sample Cresult in different hydrogel properties. The primary differences relateto the absence of desiccation, grinding, washing and drying steps forsamples A and B. Without being bound by theory, this is believed toresult in inhibition of the double anhydrification/double esterificationprocess, which requires the elimination of water from the reactionmixture, as water itself is a product of the reaction. This is alsobelieved to result in a different stabilization mechanism for samples Aand B compared to sample C and, in turn, different molecular structureand behavior. in terms of swelling kinetic, swelling capacity andmechanical properties.

Example 7 Large Scale Preparation of Hydrogels

A process for producing hydrogel particles on a multi-Kg scale isperformed using the apparatus schematically depicted in FIG. 12. Sodiumcarboxymethylcellulose (6% wt/wt water), citric acid (0.3% wt/wt sodiumcarboxymethylcellulose) and water are mixed at room temperature andpressure in a low shear mixing vessel (mixer, 1) until a homogeneoussolution is formed. The solution is transferred to trays so as tomaintain a solution depth of about 30 mm. The trays are placed in anatmospheric forced air oven (tray dryer, 2), and dried for 16 to 24hours at 85° C. The temperature is then lowered to 50° C. until dryingis complete. The total drying time is about 60 hours. The resultingresidue is in the form of a sheet, which is ground using a coarse mill(3) and fine mill (4) and sieved (sieve, 5) to provide a samplecomprising particles of size between 100 and 1600 μm. The particles areplaced in a crosslink reactor (6) and maintained at 120° C. andatmospheric pressure for 3 to 10 hours. The resulting hydrogel istransferred to a wash tank (7) and washed at ambient temperature andpressure with an amount of water between 150 and 300 times the polymerweight. The free water is removed from the hydrogel by filtration(Filter, 8). The hydrogel is placed on trays at a thickness of about 40mm. The trays are placed in an atmospheric forced air oven (tray dryer,9) and dried for 24-30 hours at 85° C. The temperature is then loweredto 50° C. until dry. The total drying time is about 60 hours. The driedmaterial is ground into particles using a fine mill (10) andmechanically sieved (sieve, 11) to obtain particle fractions between 100and 1000 μm.

Using this general process and starting with greater than 4 Kg of sodiumcarboxymethylcellulose, the yield was over 70% of powder with a particlesize range between 100 and 1000 um. The powdered hydrogel product metthe product specifications as detailed in Table 14.

TABLE 14 Final Product Specifications Attribute Specifications MethodAppearance Yellowish to light brown Visual glassy powder Media uptakeNLT 50x reported as g/g 1 g in 200 mL SGF/water 1:8 for 30 minutesParticle size At least 95% of particles Estimation by analyticaldistribution between 100 and sieving 1000 μm Tapped density NLT 0.6 g/mLBulk density and tapped density of powders. Elastic NLT 350 Pa Analysisof swollen particles modulus with parallel plate rheometer Loss ondrying NMT 10% Loss on drying at 100° C. for 20 minutes MicrobiologyTotal Aerobic Microbiological examination Microbial count NMT ofnon-sterile products, 1000 CFU/g microbial enumeration Total CombinedYeasts/Molds NMT 100 CFU/g Absence of E. coli in 1 g

Example 8 Study of the Effect of Washing Procedure on the Properties ofCitric Acid Cross-Linked Carboxymethylcellulose

Hydrogel samples were prepared according to the procedure described inExample 7.

100 g dried hydrogel was mixed with 5000 g deionized water for 90minutes. This wet slurry was passed though a large mesh stainless steelfilter (500-1000 um pore size). 2.31 Kg of wet hydrogel was collected.The filtrate was saved for future analysis. The wet gel was added againto 5000 g deionized water for additional 120 minutes. The material wasfiltered as before and 2.28 Kg of gel was collected. The filtrate wassaved for future analysis.

The filtrate from the two washes was poured into glass drying pans andplaced in a forced air oven overnight to dry at 105° C.

Results: First Wash:

-   -   Tare: 764.3 g    -   Sample weight: 778.4 g    -   Difference: 14.1 g

Second Wash:

-   -   Tare: 764.3 g    -   Sample weight: 764.4 g    -   Difference: 0.1 g

Observations:

It is possible that some gel particles slipped through the filter, as asmall number of particles were observed in the first filtrate sampleupon drying. No gel particles were observed in dried residue of thesecond filtrate.

Conclusions:

-   1) About 15% of the CMC does not react and is washed out of the gel.-   2) In this experiment, 99.5% of the unreacted CMC is washed out    after 90 minutes of washing.

Example 9 Effect of Citric Acid Concentration on Hydrogel Properties

Sodium carboxymethylcellulose was mixed in aqueous solution with citricacid at different concentrations. The mixture was dried in the oven (45°C.) and then ground to form 100 1000 μm particles. These particles werecross-linked at 120° C. for 4 hours. The elastic (Storage) modulus (G′),Loss Modulus (G″), viscosity (η), and media uptake in SGF/water 1:8(recorded after 30 minutes) were determined for the gel particles.

The results are set forth in Table 15, which presents the NaCMCconcentration by weight relative to the weight of water and the citricacid concentration by weight relative to the weight of NaCMC. MUR is themedia uptake ratio in water:simulated gastric fluid 8:1.

TABLE 15 NaCMC CA (wt/wt (wt/wt G′ G″ Viscosity water) CMC) MUR Particlesize (Pa) (Pa) (Pa * s) 6% 0.05%  124.53 100-500  75 22 30 6% 0.05% 130.10 500-1000 79 22 26 6% 0.1% 67.83 100-500  1012 325 246 6% 0.1%73.38 500-1000 1163 357 410 6% 0.15%  58.79 100-500  1524 447 279 6%0.15%  61.40 500-1000 1612 432 536 6% 0.2% 40.52 100-500  3180 1083 3886% 0.2% 40.24 500-1000 2231 704 534 6% 0.25%  33.56 100-500  3364 1456567 6% 0.25%  34.12 500-1000 3289 1567 646 6% 0.3% 27.60 100-500  44561920 829 6% 0.3% 27.32 500-1000 4267 1835 981 6% 0.4% 20.12 100-500 6259 2517 1172 6% 0.4% 19.56 500-1000 5348 1932 1489

The above data were analyzed using an Experimental Design Software (JMP,by SAS Institute, Inc). The results are shown in FIG. 13, which showsthat increasing citric acid concentration results in increasing elasticand viscosity moduli, but at the expense of swelling capacity.Desirability, which takes into account target ranges of eleasticmodulus, viscosity modulus and swelling capacity, or media uptake ratioin SGF/water 1:8, is maximized at a citric acid concentration of 0.3% byweight relative to the weight of carboxymethylcellulose, with relativelylittle change from about 0.15% to about 0.35%.

Conclusions:

The results show a strong relationship between the concentrations ofNaCMC and citric acid. When optimized for human therapeutic benefitswith elastic modulus similar to masticated food (1000-5000 Pa forunwashed particles and 350-1000 Pa for washed particles) the maximummedia uptake was between citric acid concentrations from 0.15% to 0.3%at 6% NaCMC.

Example 10

To validate the results of Example 9, the study was repeated using 6%NaCMC with 0.3% CA. The hydrogel was prepared as described in Example 9and then was washed three times in deionized water and then desiccatedagain. The results, which are set forth in Table 16, demonstrated goodmedia uptake of over 70 in SGF/water 1:8 with an elastic modulus ofgreater than 1000 Pa. Table 17 presents the results of a study of theswelling kinetics of this material in SGF/water 1:8. The resultsdemonstrate rapid swelling of the hydrogel in this medium.

TABLE 16 MUR G′ at G″ at η at in DI MUR in 9% MUR in 10 rad/s 10 rad/s0.5 rad/s water NaCl SGF/Water 1:8 [Pa] [Pa] [Pa * s] 138.46 50.99 72.151093.53 153.38 319.99

TABLE 17 Media uptake ratio SGF/Water 1:8 (relative to value at MediaUptake time 30 min.)  5 min 53% 10 min 79% 15 min 91% 20 min 94% 30 min100%

Example 11

Hydrogels of citric acid-cross-linked carboxymethylcellulose wereprepared as generally described in WO 2009/021701. Aqueous solutions of2% sodium carboxymethylcellulose (wt/wt water), 1% citric acid (wt/wtcarboxymethylcellulose) and either no sorbitol or 4% sorbitol (wt/wtcarboxymethylcellulose) were agitated, the solution was poured into apan, dried at 30° C. for 24 hours and then maintained at 80° C. for 24hours. The resulting hydrogels were washed and dried in acetone, asdescribed in WO 2009/021701.

The properties of the hydrogel prepared with 4% sorbitol are set forthin Table 18. The properties of the hydrogel prepared in the absence ofsorbitol could not be determined because this hydrogel dissolved inwater during the washing step.

TABLE 18 Swelling ratio in Swelling Swelling ratio G′ at G″ at η atDemineralized ratio in SGF/Water 10 rad/s 10 rad/s 10 rad/s water inNaCl 1:8 [Pa] [Pa] [Pa * s] 169.91 50.99 59.32 2219.37 266.74 517.10These results demonstrate that at low concentrations ofcarboxymethylcellulose, for example 2% (wt/wt water), production of astabilize hydrogel requires a physical spacer, such as sorbitol, ahigher concentration of citric acid and/or a higher cross-linkingtemperature. It is believed that sorbitol acts as a plasticizer for thecarboxymethylcellulose, increasing chain mobility and thereby reducingthe energy required for cross-linking.

Example 12

Hydrogels were prepared as described in Example 9 atcarboxymethylcellulose concentrations of 2 to 6% by weight relative towater and a citric acid concentration of 0.1% by weight relative tocaboxymethylcellulose. The cross-linking time was either 4 hours or sixhours. The hydrogel products were not washed. The hydrogels werecharacterized by media uptake in SGF/water 1:8, G′, G″ and η. Theresults are set forth in Tables 19 and 20.

TABLE 19 NaCMC (%) CA (%) Time MUR G′ G″ η 2 0.1 4 NA NA NA NA 4 0.1 4NA NA NA NA 6 0.1 4 51 1738 171 144 6 0.1 4 47 2171 228 313

TABLE 20 NaCMC (%) CA (%) Time MUR G′ G″ η 2 0.1 6 38 2501 390 290 4 0.16 47 2283 246 497 6 0.1 6 39 2461 291 302The results demonstrate that at low concentrations of citric acid alonger cross-linking time is needed. Increasing the CMC concentrationleads to a stabilized hydrogel compared to a hydrogel prepared with alower concentration of CMC and a longer cross-linking time.

What is claimed:
 1. A method for producing a polymer hydrogel,comprising the steps of: (a) preparing an aqueous solution of a watersoluble polysaccharide derivative and an amount of polycarboxylic acidless than about 0.5% by weight relative to the weight of thepolysaccharide derivative; (b) agitating the solution; (c) isolating apolysaccharide derivative/polycarboxylic acid composite from thesolution; and (d) heating the polysaccharide derivative/polycarboxylicacid composite at a temperature of at least about 80° C., therebycross-linking the polysaccharide with the polycarboxylic acid.
 2. Themethod of claim 1, wherein the polysaccharide/polycarboxylic acidcomposite is granulated prior to conducting step (d).
 3. The method ofclaim 1, wherein the polysaccharide derivative is present in thesolution of step (a) at a concentration of about 4% or greater 8% byweight relative to water.
 4. The method of claim 1, wherein thepolycarboxylic acid is present in the solution of step (a) at aconcentration of about 0.3% or less by weight relative to the weight ofthe polysaccharide derivative.
 5. The method of claim 1, wherein thepolycarboxylic acid is present in the solution of step (a) at aconcentration of about 0.05% to about 0.3% by weight relative to thepolysaccharide derivative.
 6. The method of claim 3, wherein thepolysaccharide derivative is present in the solution of step (a) at aconcentration of about 4% to about 8% by weight relative to water. 7.The method of claim 6, wherein the polysaccharide derivative is presentin the solution of step (a) at a concentration of about 5% to about 7%by weight relative to water.
 8. The method of claim 7, wherein thepolysaccharide derivative is present in the solution of step (a) at aconcentration of about 6% by weight relative to water.
 9. The method ofany one of claims 1 to 8, wherein the polycarboxylic acid is present inthe solution of step (a) at a concentration of about 0.15% to about 0.3%by weight relative to the polysaccharide derivative.
 10. The method ofany of claims 1 to 9, wherein the polysaccharide derivative iscarboxymethylcellulose.
 11. The method of claim 10, wherein thepolycarboxylic acid is citric acid.
 12. The method of claim 11, whereinthe carboxymethylcellulose is present in the solution of step (a) at aconcentration of about 6% by weight relative to water and the citricacid is present in the solution of step (a) at a concentration of about0.15% to about 0.3% by weight of the carboxymethylcellulose.
 13. Themethod of claim 12, wherein the citric acid is present in the solutionof step (a) at a concentration of about 0.3% by weight of thecarboxymethylcellulose.
 14. The method of claim 1, wherein thepolysaccharide derivative is a combination of hydroxyethylcellulose andcarboxymethylcellulose.
 15. The method of claim 13, wherein thepolycarboxylic acid is citric acid.
 16. the method of claim 1, furthercomprising the step of grinding the polysaccharidederivative/polycarboxylic acid composite to form composite particlesbefore conducting step (d).
 17. A method for producing a polymerhydrogel, comprising the steps of (a) preparing an aqueous solution ofcarboxymethylcellulose, wherein the concentration of thecarboxymethylcellulose is at least 4% by weight relative to water, andan amount of citric acid less than 0.5% by weight relative to the weightof the polysaccharide derivative, (b) agitating the solution; (c) dryingthe solution to form a carboxymethylcellulose/citric acid composite (d)granulating the composite to produce composite particles; (e) heatingthe composite particles at a temperature of at least about 80°, therebycross-linking the carboxymethylcellulose with the citric acid andforming the polymer hydrogel.
 18. The method of claim 16, wherein theconcentration of the carboxymethylcellulose in step (a) is from about 4%to about 8% by weight relative to water, and the citric acidconcentration in step (a) is from about 0.15% to about 0.3% by weightrelative to the weight of the carboxymethylcellulose.
 19. The method ofclaim 17, wherein the concentration of the carboxymethylcellulose instep (a) is about 6% by weight relative to water, and the citric acidconcentration in step (a) is about 0.3% by weight relative to the weightof the carboxymethylcellulose.
 20. The method of claim 16, furthercomprising washing the polymer hydrogel with water.
 21. A polymerhydrogel produced by the method of any one of claims 1 to
 15. 22. Apolymer hydrogel produced by the method of any one of claims 16 to 19.23. A polymer hydrogel consisting essentially of carboxymethylcellulosecross-linked with citric acid having one or more of the following: (a) atapped density of at least 0.5 g/cm³; (b) a media uptake ratio insimulated gastric fluid/water (1:8) of at least about 50 at 37° C.; (c)an elastic modulus of at least about 350 Pa.
 24. The polymer hydrogel ofclaim 23, which is less than about 10% water by weight.
 25. The polymerhydrogel of claim 23, wherein 95% of the hydrogel by weight consists ofparticles in the size range of 100 μm to 1000 μm.
 26. A polymer hydrogelconsisting essentially of carboxymethylcellulose cross-linked withcitric acid characterized by at least one of the following: (a) a ratioof bonded citric acid to carboxymethylcellulose 0.05% to 1% wt/wt; and(b) a degree of cross-linking from about 2.5×10⁻⁵ mol/cm³ to about5×10⁻⁵ mol/cm³.
 27. The polymer hydrogel of claim 24 having a ratio ofbonded citric acid to carboxymethylcellulose of 0.1% to 0.4% wt/wt. 28.The polymer hydrogel of claim 25 having a ratio of bonded citric acid tocarboxymethylcellulose of 0.225% to 0.375% wt/wt.
 29. The polymerhydrogel of claim 24 having a degree of cross-linking from about 4×10⁻⁵mol/cm³ to about 5×10⁻⁵ mol/cm³.